Control of adaptive immunity by the innate imunne system

NA TURE IMMUNOL OGY VOLUME 16 NUMBER 4 APRIL 2015 343 Control of adaptive immunity by the innate immune system Akiko Iwasaki & R uslan M edzhitov Microbial infections are recognized by the innate immune system both to elicit immediate defense and to generate long-lasting adaptive immunity . T o detect and respond to vastly different groups of pathogens, the innate immune system uses several recognition systems that rely on sensing common structural and functional features associated with different classes of microorganisms. These recognition systems determine microbial location, viability , replication and pathogenicity . Detection of these features by recognition pathways of the innate immune system is translated into different classes of effector responses though specialized populations of dendritic cells. Multiple mechanisms for the induction of immune responses are variations on a common design principle wherein the cells that sense infections produce one set of cytokines to induce lymphocytes to produce another set of cytokines, which in turn activate effector responses. Here we discuss these emerging principles of innate control of adaptive immunity . Inna te control o f adap tive imm unity is no w a well-established paradigm. First in troduced by Cha rles J aneway J r . in 1989 (ref. 1), it sta tes tha t recog - nition o f conserved featur es of micr obial pathog ens b y the innate imm une system is media ted by pa ttern-recogni tion recept ors (PRRs), which det ect conserved pathogen-associated mol ecular patterns (P AMP s), such as bac - terial and fungal cell-wall compon ents a nd viral nucleic acid s. Detection of P AMPs b y PRRs leads to the induction of in flammato ry responses and inna te host defenses. I n additio n, the sensing o f microbes by PRRs expre ssed on an tigen-pr esenting cells, particularly dendritic cells (DCs), leads to the activatio n of ada ptive imm une responses. Several classes of PRRs hav e now been iden tified and characterized in some detail. These include T oll-like r ecepto rs (TLRs), nuc leotide-bindin g oligom erization domain (N od)-, leucine-rich repeat–con taining recep tors (NLRs), RI G-I- like recep tors (RLRs), C-type lectin recepto rs (CLRs) an d AIM-2 like r ecep - tors, as w ell as a family o f enzymes that function as in t race llular sensors o f nucle ic acids, includin g O AS protein s and cGAS 2–4 . The ph ysiological role of differ ent PRRs in the sensing of m icrobes an d the induction o f adap tive immune r esponses co ntin ues to be inv estigat ed, but in g eneral, the ava il - able evidence uneq uivocally su pports the view that PRR -mediat ed sensing instructs the adaptiv e immune r esponses: specif ically , PRRs determine the origin of the an t ig ens recognized by the a ntigen r eceptor s expr essed on T cells and B cells, as we ll as determine the type of infection encoun tered, and instruct lym phocytes to induce the a ppr op riate effector clas s of the immune r esponse. Studie s over the past decade ha ve also reveale d several im portant aspects of imm une system ’ s function that r e q uire a n expanded view of the inna te contro l of ada ptiv e immuni t y . Fo r exam ple, the type 2 immune r esp o nse induced b y parasitic w orms an d allergens a ppears to be largely in dependent of P RRs, perhaps because m ulticellular paras ites lack molecular structures tha t are bo th conserved across differen t grou ps of parasi tes and di stinct from the host o rganism. S imilarly , allergens are not micr obial in origin, lack con ser v ed structural featur es and ind uce type 2 immune re sponses through mech anisms tha t rema in large ly un k nown 5 . Another big puzzle is the a ppar ent a bility of the imm une system to dis tinguish between beneficial commensal microorga nisms and pathog enic microor ganism s. Both types of microbes expre ss P AMPs and ar e detectable by P RRs; how ever , the outco me of their r ecognition can depend on addi tional characteristics, s uch as in vasivenes s and pr o - duction of t oxins. Recen t pr ogress in under standing the com plexity and div ersity of co mmensal microbiota sugges ts that perha ps the clas - sic notion of ‘ pathogens ’ is in fact applica ble only to ra re o utliers of the entir e spectr um o f the microorg anisms tha t c a n colonize a ma mmalian host. H oweve r , this does not mean that the imm une system is concerned only with these few bad ap ples; even the no rmal commensal inhabi t - an ts need to be contin uousl y monit ored a nd someho w ‘ manag ed’ b y t he immune sys tem to pr e ve nt their ou t gr owth and mi schief 6–8 . Man y discoveries made in the field over the past decade call fo r a mor e com plete a nd nua nced pictur e of innate in struction of the ada p - tive imm une respon ses. Her e we r eview s o me of the r ecent develo p- ments in s tudies of inn ate co ntr ol of ada ptiv e immuni ty . W e highlight some emerging co ncepts tha t expand the pat tern-recognitio n paradigm. Finally , we discuss some o f the major g aps an d unknowns. Recognition by the innate immune system Microb ial targets o f recognition b y PRRs are structurally diverse and include co mp lex polysaccharides, glyco lipid s, lipopr oteins, nucleo - tides and n ucleic acids. Several families of PRRs det ect these str uctur es through the use of distinct liga nd-recognition d omain s, includin g leu - cine-rich repeats, C-type lectin domains a nd various n ucleic acid–bind - ing dom ains. I n addition to being ch aracterized by thei r structure an d Howard Hughes Medical Institute, Department of Immunobiology , Y ale University School of Medicine, New Haven, Connecticut, USA. Correspondence should be addressed to A.I. ( akiko.iwasaki@yale.edu ) or R.M. ( ruslan.medzhitov@yale.edu ). Received 26 January; accepted 10 February; published online 19 March 2015; doi:10.1038/ni.3123 REVIEW npg © 201 5 Nature America, Inc. All rights reserved. 344 V OLUME 16 NUMBER 4 APRIL 2015 NA TURE IMMUNOL OGY gous t o the function of Gua rd pr otein s in plan t immun ity 24 . The re are several advantag es of this mode of r ecognition. Firs t, it elimina tes the need for a very large n umber of specific recepto rs fo r each of the struc- turally diver se virulence fac t ors, to xins or allergens. In stead, the com - mon activities o f these agents a re detected and trigger the r esponse. Second, the recognition o f functional feat ures, when co mbined wi th patt ern recognition, can inf orm the imm une system tha t the microbe is a pathogen. Fin ally , the recognition o f functional feat ures ma y b e the only a vailable mode of r e cogni tion of m u l ticellular parasi tes that lac k structurally invaria nt tar gets fo r direct patt ern recognition. I nstead, they may ha ve some co mmon activities, suc h as excretio n of cyste - ine pr oteases and disrup tion of basemen t membranes. These types of effects on the host tissues ma y a lso be shar ed with certain classes of allergens an d may be detectable thro ugh commo n sensing path ways. These path ways most pr obabl y ov erlap wi th path ways tha t sense tissue damage , which are designed to det ect common co nsequences of tis - sue damag e rather than the s tructure of the dama ging agen ts 25 . Th us, PRR -mediated recognition in co mbin ation wi th the recognition o f functional feat ures leads to the type 1 immun e respon se to micro - orga nisms (viruses, bacteria, fungi and possibly pr otozoa), whereas the recognition o f functional feat ures in the absence o f PRR signal leads to the type 2 immune r esponse and tiss ue-repair r esponse to macro parasites. I ndeed, the cas e ha s been made that type 2 immuni ty to parasitic w orms is in ma ny wa ys a sp ecialized form o f tissue-repair resp onse 26,27 . Finally , tissue damage ind uces a tissue-r epair respon se that can i nv olve the activa tion of specialized arms of inna te and adap - tive imm unity , such as activation o f regulat ory T cells, group 2 inna te lymp hoid cells (ILC2 ce lls), eosinophils an d M2 macrop hages b ut does not lead to ada ptive im muni ty 28–31 ( Fig. 1 ). In addi tion to pa ttern recognitio n, another s trategy for r ecognizing structural featur es is thro ugh missing-self recognitio n 32 . This mode of discriminatin g self versus no n-self is ancien t; it is used, for exam - ple, by bacterial restriction-modification system to defend a gainst parasitic D N A of phages an d other bacteria. In this stra teg y , methyla - tion of adenin e nucleo tides in specific DN A sequences pr otects self DN A f r om clea vage by restriction endo nucleases, ther eby permit ting destruction of only f oreign D N A. In ma mmalian imm unity , miss - ing-self recognitio n is importan t in mul tiple settings. This s trategy is used by na tural killer (NK) cells to detect infected or stressed cells 32 . Inhib ito r y r ecepto rs on NK cells co ntainin g an imm unorecep tor tyro - sine-based inhibito ry motif detect major histocom patibility com plex class I molecules on tar get cells to a void killing health y uninfected specificity , PRRs ar e characterized b y their tissue-specific expr ession, a s well as by their localiza tion in distinct cellular com part me nts, incl ud - ing the plasma m embra ne, endoso mes, lysosomes a nd cytosol 9 . These differences in exp ressio n pat terns ar e rela ted to two gene ral modes of recognition b y t he in nate im mune sys tem and imm une res ponses: cell- intrinsic r ecognition is media ted by in tracellular cytosolic sensors tha t operat e in infected cells. All cell types that can be infected by a given class of pa thogens exp ress the co rrespondin g sensors (fo r exam ple, sen - sors of viral n ucleic acids). Cell-extrinsic recognitio n does not requir e that the cell expr essing P RRs be infected. Inst ead, the PRRs in volved in cell-extrinsic recognition (f or exam ple, TLRs and CLRs) are exp ressed in cells specialized in p a thogen detection, such as surface epithe lia and myelo id cells . The detection of extracell ular pathogen s is mediated ma inly by PRRs expr essed on the plasma me mbra nes of mac rop hages, DCs and o ther cell types. These PRRs, including TLR1, TLR2, TLR4, TLR5 a nd TLR6, and CLRs, incl uding dectin-1, dectin-2 and mincle, ar e specialized in the recognition o f commo n com ponen ts of bacterial and fungal cell walls, such as lipo polysaccharides, bacterial lipopeptides, lipot eichoi c acids, flagellin, glycolip ids and b -glucans. Cell-extrinsic recognitio n of viruses is mediated b y TLR3, TLR7, TLR8 and TLR9, which a re expr essed in the endosomes, wher e they detect viral nucleic acids. Recognition b y TLRs and CLRs is gen erally not dependen t on micr obial viability , replica tion or in vasiven ess and th us it can det ect a broad spectrum of microbial P AMPs rega rdless o f their origin (tha t is, whether the P AMPs ar e pro - duced by pa thogenic o r commensal micr obes, dead or alive micr obes, and rep licating o r quiescen t microbes). Cytosolic sen sors of viral n ucleic acids detect viral RN A (RLRs) and viral DN A (c ytosolic D N A sensors) in inf ected cells 10–12 . In tracellula r bacteria can be sensed by the endoplasmic r eticulum membra ne - residen t ad a ptor STING thr ough the detection of bacterial cyclic di- guanylate monophosp hate 13 . The same pa thwa y is ac tiva ted by the rela ted dinuc leotide cyclic AMP -GMP , which is p roduced b y cGAS in respon se to the intracell ular recogni tion of D N A 3 . In vasive bacteria are also recognized by the cytosolic PRRs N o d1 a nd N od2, as well as by o ther NLRs tha t detect bacterial P AMPs (such a s peptidogly - can fragments a nd flagellin) introd uced into the cytosol 14,15 . S ome NLRs detect intracellular bacterial and viral infections a nd induce the inflammasome com plex, which leads to cas pase-1-dependent pr ocess - ing and secretio n of members o f the int erleukin 1 (IL-1) family of cytokines, such as IL-1 b and IL-18. The r ecognition o f microbes b y the intracellular senso rs generally depends o n microb ial invasi veness, viability an d, in some cases, rep lication 16–19 . Thus, this c lass of PRRs is mor e restricted in what they can sense. M ost P AMP s can be sensed both by cell-extrinsic path ways (mediated by TLR) a nd by ce ll-intrinsic path ways (media ted by RLRs, NLRs a nd cytosolic DN A s en sors): this is the case for viral n ucleic acids, lipo polysaccharide (LPS) an d flagel - lin. Pres umably the two m odes of recognitio n hav e evolved to p ro vide differen t signals to the immun e system (discussed below). In addi tion to the recogni tion of structural fea tures (tha t is, direct PRR -mediated recognition o f microb ial ligands), the inna te immune system can detect pa thogens thro ugh the recognition o f functional feat ures, b y sensing functional cha racteristics indicativ e of a patho - gen ’ s presence, such as co mmon effects of virulence factors 20 . The best availab le exam ple of this mode o f sensing is activa tion of the NLRP3 inflammasome by bacterial pore-f orming exo to xins as well as b y viroporins, whic h form ion c hannel s in the membra ne of hos t intra - cellular organelles 21–23 . S en sing of enzyma t ic activi ties of allergens i s another exa mp le of functional fea ture r ecognition. I t is likely that m u l- ticellular para sites a re det ected by the imm une syst em mainly thr ough this mode of sensing as w ell. This type of detection ‘by p ro xy’ is analo - Tissue damage Tissue- re pair response Helminthes Allergens To xins Virulence factor s Viroporins Immune response F unctional featur e recognition Structural featur e recognition Immune response Microbial P AMPs Figure 1 Recognition of structural and functional features. Sensors of the innate immune system recognize infectious agents through detection of unique molecular structures associated with the pathogens (structural feature recognition) or through detection of the characteristic functional activities (functional feature recognition) associated with the infection. The process of infection is often accompanied by tissue damage caused by the pathogens or by the immune response to pathogens. T issue damage induces a tissue-repair program that can include some specialized immune responses. REVIEW npg © 201 5 Nature America, Inc. All rights reserved. NA TURE IMMUNOL OGY VOLUME 16 NUMBER 4 APRIL 2015 345 only in vasive bacteria, bu t not l uminal bacteria, trigger TLR stimula - tion in the int estinal mucosa. I n addition, in r esponse to dam age or stress, ep ithelial cells release cytokines, incl uding IL-25, IL -33, IL-1 a and TSLP , to activat e local ILCs and memory lymph ocytes 39 . Beneath the epithelial lay er , in the lamina pr opria, r eside DCs, mac - rop hages an d mast cells tha t are specialized in detecting pathogens that ha ve cro ssed the epithelial barrier . These cells expres s PRRs that induce the secretion o f inflammato ry c yto kines and chem okines that facilitate the r ecruitment o f monocytes, neutr ophils, eosino phils and basophils from the cir culation. TLR5 exp ressed on the surface o f DCs detects extracellular bacteria through flagellin, activating the r elease of cytokines, chemokines a nd an timicrob ial peptides 40 . If the bacterium can in vade the host cell successfully , f lag ellin in the cytosol is recog - nized by N AIP5 and N AIP6, which ph ysically associate with NLRC4 to trigger activation o f inflammasomes 41,42 . This s ignifies to the host that the bacteria has secretio n systems ca pable of injecting effector molecules into the cytosol, a nd such inf ection is met with a grea ter degree of ur gency , w hic h causes the activa tion of inflammasome s and caspase-11 and the induction o f pyr opt osis 43 . The am plification in the num ber of leukocytes at the sit e of infection en ables ra pid co ntain - ment o f replica t in g pathogen s through pha gocytosis, secretion of to xic granules, a nd lysis o f pathogen s and infected cells. When suc h local defenses are ins ufficient to con t a in the pathogen, the immune sys tem engag es a systemic-level acu te-phase res ponse to comba t the spr eading pathoge n. Bacteria in the bloo ds tream ar e recog - nized immediatel y by mo nocytes and neutr ophils thro ugh TLRs, NLRs and CLRs. A c tiva t io n of these PRRs leads to enha nced phagocytosis, degranula tion, res pira tory burst and killing o f bacterial, fungal and protozoan p a thoge ns 44 . Eng agemen t of TLRs also induces the f or - matio n of neutr ophil extracell ular traps con sisting of extruded DN A, which entra p bac t eria and moun t the rapid ind uction of inflamma tor y cytoki nes and chemokines 45 . The inflammato r y cytokines IL-1 b , TNF and IL-6 act o n the liver an d the central nervous system. I n t he brain, these cytokines induce sickness beha v io r and f ever 46 . In the liv er , these cytokines induce the pr oduction of acu te-phase res ponse pr oteins, includin g C-reactive pr otein, serum am y lo id pr otein an d mannose- binding p ro tein, to pr omo te pathog en clearance thr ough com plemen t activation a nd phag ocytosis 47 . A parallel ana tomical regula t io n of inna te s en sing exists f or viruses. V ir u ses that infect the epi thelial cells trigger c yt osolic nuclei c acid sen - sors to ind uce local type 1 interfero n respon se. In additio n, secreted cytokines enter the cir culation an d induce in terfer on-stim ulated genes in distal tissues to incr ease hemato poiesis a nd prepa re fo r systemic viral spread 48 . W hen this local response fails t o restrict the virus rep - lication, the viral load in the bloodstream, o r ‘virem ia ’ , triggers a ro bust systemic type 1 int erfero n respon se. The systemic virus infection is patro lled by plasmacytoid DCs. These plasmacytoid DCs ar e absent from peripheral tiss ues at st eady state , but a re fo und in the circulatio n, are co nsti tuti vely localized in the red p ulp of the s pleen 49,50 and are specialized in responding to blood-borne viruses 51 . Once TLRs are engaged in plas macytoid DCs, they rapidly secrete lar ge amo unts o f type 1 interfer ons, which a re key to su pp ressin g viral load throughou t the bod y . Although the mecha nisms b y which mul ticellular parasit es are detected are no t yet known, the def ense strat egies used also dem - onstra te clear compartmen t-specific effects. Thus, the detection of macro parasites in the in testinal and resp irato ry t racts p rom otes their expulsion thr ough increased pr oduction of m uc us a nd peristalsis, whereas the detection of para sitic eggs in the tissues can p romo te their sequestra tion thro ugh granulo ma fo rmatio n 52 . Finally , the detection of tick bi tes triggers basophil-media ted acquir ed tick resistance 53,54 . ‘ self ’ cells. V iral infect io n and va rious fo rms of stres s reduce the sur - face expres sion o f major h istocom patib ility com plex class I, which flags these cells for NK cell - mediated l ysis 33 . Other exam ples of this include ma crop hages tha t use inhibit ory receptors based on imm u - nor eceptor tyr osine-based inhibito ry motifs to detect self ligands to avo id the phag ocytosis and killing of normal cells 34 ; the complem ent system uses a similar stra tegy to preven t lysis o f cells that exp ress com plemen t inhibit ory prote ins, such as CD46 a nd CD55; factor H of the alterna t i ve com plemen t p a t h way detects sialic acids presen t on host cells bu t absent o n most bacteria and fungi and inhi bits activa - tion of the C3 co nv ertase of the alternativ e path way . Sialic acids are also detected by the Siglec family of inhib ito r y r ecepto rs, such as CD22 expre ssed on B cells 35 , which helps t o determine the origin of the an tigen recognized by the B cell a ntigen r ecepto r . I t is int er - esting to no te that mis sing-self recognitio n is often used to inhibi t effector respo nses, such as ph agocytosis, cell killing and com plemen t activation, which in dicates tha t missing-self–recognition pa thwa ys generally opera te along wi th the pathwa ys that activate these effector respon ses. In some cases, the activa ting path ways are media ted by recepto rs con t a ining an imm unoreceptor tyr osine-based activation motif; in other s, they are ind uced by PRR -based pathway s (as is the case of the PRR pr operdin in the alt ernative co mp lement pa t h way 36 ). In summa ry , different modes of r e cogni tion by the inna te immune system fo rm distinct layer s of sensing b y the immun e system tha t pro - vide requisi te info rmation t o the adap tive imm une system. W orkin g in differen t comb inatio ns, the sensing pa thwa ys of the innate imm une system instruct the activatio n of rel evant effector r esp o nses of the ada p - tive imm une system. Recognition in different compartments Microb ial pathogen s enter the h ost via mucosal surfaces, through a breach in the s kin or via bit es of insect vectors. T o r ecognize and respon d to in vasion b y vastly differen t classes of infectious agen ts, inna te sen - sors ar e strategically locat ed in distinct anat omical, tissue , cellular and subcellular com p a rtments. The an ato mical com partment in which the pathogen is r ecognized informs the host o f the degree of threa t it poses. Microorga nisms in the lume n of the gut do no t trigger inflamma - tion, whereas those that ha ve crossed the epithelial lay er induce a local inflammato ry response. M oreo ver , pathog ens in the bloodstream signify a breac h in barrier and ar e met with a full-blown systemic r esponse. This com partment-specific out come of sens ing by the inna te immune system is media ted by distinct sen tinel cells that a re stra tegically located to detect the location of pa t ho gens. The first sur v eillance system encoun tered by pa thogens en tering the host thro ugh mucosal surfaces is the sup ra-epithelial pha gocytes. Specialized monon uclear pha gocytes pro vide surveillance in cert a in mucosal surfaces abov e the epithelial la yer . In the a ir wa ys, alveolar macro phages a re si tuat ed inside the lumen f or access to a irborne pathogen s, whereas in the int estine and r espira tor y tracts, DCs form tight jun ctions with the ep ithelial cells a nd extend dendrites i nto the lume n 37 . The epi thelial cells constit ute the next leve l of surveillance and ar e often the targ et of rep lication b y a variety of pathogens. E ven a non- epitheli um-trop ic p a t ho gen mu st cross the ep ithelial barrier to access its rep licativ e niche. Th us, the recognitio n of pathog ens b y epithelial cells informs the h ost of a br e ac h in the first barrier . Epi thelial cells are equi ppe d wi th PRRs that ind uce chemokines a ble to r ecruit cir - culating leukocytes to initiat e an inna te defen se. Colonic epi thelial cells expre ss small amoun ts of TLRs, and some TLRs, incl uding TLR2, TLR3, TLR4 and TLR5, ar e selectively expr essed on the basolat eral sur - face of in testinal epi thelial cells 38 . This expr ession pa ttern ens ures tha t REVIEW npg © 201 5 Nature America, Inc. All rights reserved. 346 V OLUME 16 NUMBER 4 APRIL 2015 NA TURE IMMUNOL OGY neity , including DC subset - specific expres sion of P RRs and pr o d uction of signals, incl uding cytokines, in volv ed in differen tiation o f T cells into effecto r cells 55–57 . I n addition, several tran scriptional mas ter regula - tors o f DC lineages hav e been defined, which has pro vided the means for el ucidating their function s in v ivo 58,59 . Tissue-residen t D Cs con sist largel y of Langer hans cells, CD103 + DCs and CD11b + DC s. Langer hans cells marked b y CD207 reside in the s tratified squamous ep ithelium of the skin and m ucosa l tis sues. W ithin the dermis and subm ucos a, CD103 + CD207 + CD11b – DCs (developmen tally dependent o n the tran - scription facto r Batf3) and CD301b + CD207 – CD11b + DCs (funct io nally dependent o n the transcription facto r IRF4) ar e presen t. In the in testine and lu ng, a third su bset of DCs are f ound benea th the epithel ial layer: The ‘choice’ of effector responses The various pa thwa ys and modes of recognition b y t he in nate imm une system discussed above p ro vide informa tion abou t microb i al p resence, viability , replicatio n, location an d virulence. Each of these parameters of recogni tion by the imm une system, as well as their comb ina tions, are cri tical for the choice o f t he a pprop riate effector r esponse. Ho w the immune sys tem int erprets these signals is not y et fully understood, bu t here we r e view several possible mechani sms. Bec a use D Cs ha ve a critical role in the ini tiation o f T cell - media ted respon ses, it has lon g been suspected that differen t DC populations migh t be specialize d f or the indu ction of differen t T cell ef f ector respo nses. M uch data ha ve accumula ted ove r the past decade on DC functional heteroge - T able 1 In vivo requirement for DC subsets in T cell responses T cell class T issue Antigen pathogen Adjuvant Route DC subset studied TF tested DC subset required? DC subset sufficient? Ref. CTL Lung OV A-coated apoptotic cell ± Poly(I:C) i.n. CD103 + Batf3 Ye s NA 65 Lung Soluble OV A None i.n. CD103 + Batf3 Ye s NA 65 Lung Soluble OV A None i.t. CD103 + NA NA Y es (A T) 64 Lung SeV None i.n. CD103 + Batf3 Ye s NA 63 Systemic Lm-OV A None i.v . CD8 a + Batf3 Ye s NA 74 Intraperitoneal T . gondii None i.p. CD8 a + CD103 + Batf3 Ye s NA 73 Skin OV A/E a -expressing C. albicans None s.s. CD207 + dDC Batf3 Ye s NA 69 Systemic or peritoneal cavity DEC205-OV A Anti-CD40 i.v . CD8 a + NA NA Yes (Ab targeting) 133 Skin OV A (self) None Skin (keratino - cyte-expressed) CD103 + NA Ye s Y es (coculture) 134 Lung O VA PR8 influenza i.n. CD103 – CD11b + NA NA Y es (coculture) 135 Lung X-31 influenza None i.n. CD207 + NA Y es (partial ↓ ) Y es (coculture) 136 T H 1 cells Skin OV A/E a -expressing C. albicans None s.s. CD207 + dDC NA Ye s NA 69 Skin MOG CF A/PTX s.c. CD103 + CD207 + GM-CSF Ye s Y es (coculture) 76 Skin MOG CF A/PTX s.c. CD103 + CD11b – Batf3 No NA 75 T H 17 cells Skin MOG CF A/PTX s.c. CD103 + CD11b – Batf3 No NA 75 Skin MOG CF A/PTX s.c. CD103 + CD207 + GM-CSF Y es (partial ↓ ) NA 76 Intestine NA NA TNBS-DSS colitis CD103 – NA NA Y es (A T) 137 Intestine NA NA NA CD103 + CD11b + Notch2, Rbpj Y es (partial ↓ ) NA 84 Intestine None None NA CD103 + CD11b + IRF4 Y es (partial ↓ ) NA 60 Lung A. fumigatus None i.n. CD103 – CD11b + CD24 + IRF4 Y es (partial ↓ ) NA 60 Intestine NA NA NA CD103 + CD11b + NA Y es ( ↓ i n huLangDT A) NA 83 Skin OV A- and/or E a -expressing C. albi - cans, anti-huLangerin- conjugated OV A and/or E a None e.c., i.p. LC NA Ye s Y es (Ab targeting) 69 Intestine O VA LPS + anti- CD40 i.p. CD103 + CD11b + IRF4 Ye s Y es (coculture) 61 T H 2 cells Lung HDM (high dose) HDM i.t. moDC CD103 – CD11b + NA NA Y es (A T) 138 Skin OV A, N. brasiliensis Papain none s.c. CD301b + NA Ye s No 86 Skin OV A, N. brasiliensis Papain none s.c. PD-L2 + IRF4 Ye s No 87 Skin FITC Acetone + dibu - tylphthalate Skin CD301b + NA NA Y es (A T) 88 Abbreviations: OV A, ovalbumin; MOG, myelin oligodendrocyte glycoprotein; s.c., subcutaneous; i.t., intratracheal; i.p., intraperitoneal; s.s., skin scarification; NA, not addressed; ↓ , reduction; Ab, antibody; A T , adoptive transfer of sorted DCs; CF A, complete Freund’s adjuvant; PTX, pertussis toxin; TF , transcription factor; HDM, house dust mite; T . gondii , T oxoplasma gondii ; C. albicans , Candida albicans ; A. fumigatus, Aspergillus fumigatus ; N. brasiliensis, Nippostrongylus brasiliensis. T able pre - pared with help of Y . Kumamoto. REVIEW npg © 201 5 Nature America, Inc. All rights reserved. NA TURE IMMUNOL OGY VOLUME 16 NUMBER 4 APRIL 2015 347 tion with an t ig en and com plete Freund ’ s adjuvan t 75,76 , which demon - strat es the key ro le of this DC subset in T H 1 cell - medi a ted responses to bacterial and fungal pathogen s ( Fig. 2 ). H ow ever , the exact iden- tity of the T H 1-primin g DCs remains con troversial. W hile one repo rt has sho wn a require ment f or CD103 + CD207 + DCs in TH1 priming 76 , another has shown that T H 1 priming occurs normally in the absence of those DCs 75 followin g immun izatio n with m yelin o ligodendrocyte glycop rot ein in com plete F reund's ad juvan t. The T H 17 subset of helper T cells is specialized in eliminatin g extra - cellular bacteria and fungal pa thogens 77,78 . The p riming of T H 17 cells begins with the engagemen t of CLRs such as dectin-1 and dectin-2 expre ssed by DCs, Langerhans ce lls and macr ophag es 79–81 . In addition to inducin g dectins, the phagocytosis of bacteria-infected apop totic cells induces the p roduction o f TGF- b and IL-6 b y D Cs, which pr o- motes T H 17 cell differen ti a tion 82 . Se v eral studies su pport the notion that CD11b + CD103 + DCs that deve lop under the co ntro l of IRF4 ha ve a key role in T H 17 cell ind uction in v ivo 60,61,83,84 . The c yt okines criti - cal for T H 17 res ponses, IL-6 an d IL-23, ar e both selectively secreted by the CD11b + CD103 + DCs 60,61 . In addi tion to the CD11b + CD103 + DCs, L a ngerha ns cells ar e necessary and sufficient for ind uc tio n of the T H 17 cell respon se to fungal pathogen s in the skin 69 . W e are temp ted to speculate that these DCs co-engage TLRs a nd CLRs to selectively induce IL-23 a nd sup pr ess IL-12 fo r optimal T H 17 cell induction in v iv o 85 . Human CD1c + DCs, the coun terpart of mouse CD11b + DCs, also express IRF4, secret e IL-23 and p rom ote T H 17 ce lls in respon se to Aspergillus fum i g at u s 60 ( Fig. 2 ). Although sensors in the inna te immune system tha t detec t p rot e- ase allergens and h elminthes a re no t yet known, st udies ha ve dem - onstra ted t ha t induction of the T H 2 cell respon se to both requires the PD-L2 + CD301b + DC p opulati on 86–88 . The CD301b + DCs comp rise the majo rity of dermal DCs that are CD207 - , and these cells requir e IRF4 for their a bility to p rom ote T H 2 cell - mediated imm unity . Of note, in CD103 + CD11b + DCs (IRF4 dependent) 60,61 . All four su bsets of tissue- residen t D Cs migrat e into the dra ining lym ph nodes and co ntribu te in a distinct manner to p riming res ponses of the ada ptive imm une system. In addi tion to the migran t DCs, within lymph oid or gans CD8 a + DCs (Batf3 dependent) a nd CD11b + DCs are cons tituti vely p resent. S tudies o f mice with specific deletions of s ubpop ulations o f DCs have r evealed an emerging view of the uniq ue capacity o f DC subpopula tions to g enerat e differen t classes of T cell r esponses ( Ta b l e 1 ). The clearan ce of viral infection relies o n c yto toxic l ymphocytes (CTLs), whose differentia tion follo ws t he en gagemen t of nucleic acid sensors, which leads to the p roduction o f type 1 interfer ons an d IL-12. Batf3-dependent CD103 + DCs found within or under va rious m ucosal epithelial cells, as w ell as the Batf3-dependent CD8 a + DCs in lymph oid orga ns, ar e requir ed for cr oss-pr esentatio n and the activa tion of CD8 + T cells 62–64 . These D Cs exp ress RLRs, NLRs a nd TLR3 bu t not TLR7 (r efs. 65,66) and pr oduce type 1 interfe ron s and IL-12 in r esponse to the r ecog - nition o f viruses and virus-infected cells ( Fig. 2 ). These cells expr ess the C-type lect in D NGR -1 (CLECL9A), which detects F-actin exposed by necrotic cells f or the up take and cros s-presen t a t io n of necr otic cells 67,68 . In addi tion to req uiring CD103 + DCs, infection with fungal pathogen s requir es Batf3-dependent CD207 + dermal DCs for CTL respon ses 69 . The CD141 hi CLEC9A + DCs found in the dermis, lung a nd liver in terstitia of huma ns shar e a transcrip tome signa tur e similar to that o f mouse CD8 a + and CD103 + DCs and ar e also superior to other DCs in cross-p riming CD8 + T cells ex vivo 70 . In addi tion, h uman CD1a + Langer hans cells induce functional ma tura tion of CD8 + T cells superior t o that ind uced by other s kin DC subsets ex v i vo 71,72 . Defense by the imm une system against in t race llular bacteria and pr o - tozoa requir es respo nses by CD8 + T ce lls and T hel per type 1 cells (T H 1 cell), which develop as a co nsequence of the en gagemen t of TLRs by P AMPs that leads t o the productio n of IL-12. CTL r esponses to bacterial and pr oto zoan infection ar e ‘ pr eferen ti ally’ ind uced by Ba tf3-dependent CD103 + DCs that produ ce IL-12 (refs. 73,74). T H 1 cell - mediated immuni t y t o fungal patho - gens depends o n Batf3-dependent dermal DCs that exp ress CD103 an d CD207 (ref. 69). The GM-CSF -dependent DC populatio n is requir ed for the ind uction of T H 1 cells a fter immuniza - T ype 1 immunity T ype 2 immunity IL -12 IL -6 IL -1 β IL -23 IL -6 IL -1 β TGF- β T ype I interf erons IL -6 IL -1 β Pathogen Cytokines Sensor PRR Lymphocyt e dif ferentiation T H 2 cell Batf3-dependent CD8 α + ,CD 10 3 + DCs (mouse) CD141 + DCs (human) Batf3-dependent CD207 + CD1 03 + dDCs Langerhans cells (mouse), IRF4-dependent CD1 03 + CD1 1b + DCs (mouse) CD1c + CD1 1b + (human) IRF4-dependent CD30 1b + CD1 1b + DCs (mouse) Langerhans cells (human) Bacteria Bacteria F ungi Helminth Allergens V enoms T H 17 cell CTL T H 1 cell RLR TLR3 CDS NLR AIM2 ? ? Dectins TLR NLR Viruses TLR NLR Pr otozoa Figure 2 The instruction of various classes of T cell responses by DCs. The development and function of DCs in vivo requires transcription factors that are critical for each stage of their differentiation program. Studies probing the requirement or sufficiency for DC subsets have suggested a relationship between the DC lineage and T cell programming. CTL responses are induced by lymphoid organ - resident, Batf3- dependent CD8 a + DCs and tissue CD103 + DCs (mouse) and the human CD141 + DC counterpart. T H 1 cell - mediated immunity requires stimulation, in a GM-CSF-dependent manner , by the CD207 + CD103 + DC subset, a minor population of dermal DCs (mouse). T H 17 responses are induced by mucosal IRF4-dependent CD103 + CD11b + DCs as well as by skin Langerhans cells, depending on the location of the pathogen (mouse). The human CD1c + DCs prime T H 17 cell responses. Finally , T H 2 cell - mediated immunity requires IRF4- dependent CD301b + CD11b + DCs (mouse). These DCs comprise the majority of dermal DC (dDC) population and are distinct from CD207 + CD103 + dermal DCs. In contrast, human Langerhans cells induce T H 2 cytokine secretion ex vivo . REVIEW npg © 201 5 Nature America, Inc. All rights reserved. 348 V OLUME 16 NUMBER 4 APRIL 2015 NA TURE IMMUNOL OGY respon se to pathogen s in infection models 98–102 , in respon se to self anti - gens in l upus m odels 103,104 , and in LPS-stim ulated and C pG-stimulated responses 98,105 . The systemi c IgA r esponse to virus-like particles con - taining RN A also requires B cell - in trinsic, bu t not DC-intrinsic, TLR7 expre s s i on 106 . In summa ry , different sensing pa t h ways of the inna te imm une system are designed to d etermine the class of inf ecting pathogens o n t he basi s of their localization, viabili ty , repli cation a nd virulence. These parameter s are sensed b y distinct sensory p a thways, ofte n operating in co mb ination, and ar e transla ted int o the signals that initia te the appr opria te types of ef fector respons es ( Fig. 2 ). Costs associated with effector responses The ‘ choice ’ of effector r esponse is determined no t only b y the class of infecting pathogen (f or exam ple, a virus versus a fungus) b ut also by the cost of the imm une res ponse 107 . The sympt oms o f infectious disease are ca us ed b y both direct pathogen-inflicted damag e, as well as b y the immune r esponse i tself, or ‘immun opatho logy’ . Immuno pathology is generally co nsider ed to be a conseque nce of ex cessiv e immun e respon se, and theref or e the magnitude a nd dura t io n of the imm une res ponse are thought to be o ptimized so as to pro vide maximal protection fro m infec - tion with minimal imm unopa thology . Ho wever , in additio n to consi d - ering the quan titativ e characteristic o f the immune r esp o nse, it m ay be important t o consider the fact that differen t ef f ector respo nses hav e differen t immun opatho logical potential; for exa mp le, defen sins and I gA secreted into in testinal lumen hav e lower cos ts to host fitness tha n do cytotoxic r esponses. I n general, all effector r esponses can be viewed on a spectr um defined b y the costs (immuno p a t ho logy) asso cia ted with their maximal deployme nt. This differ ence in the cost of effecto r respon ses ap pears to corres pond to the tem poral or der of their indu ction: low- cost respo nses are in duced first; if they are in sufficient to p reven t or clear the infection, the re sponse of next lo west cost is induced second and so on ( Fig. 3 ). Th e respon ses of highest cost ar e induced as a last resort. Some o f the res ponses tha t hav e negligible costs (s uch as secre - tory IgA an d antimicr obial peptides p roduced by s urface epithelia) ar e expre ssed constit utivel y , whereas the costly r esponses ar e induci ble. I t is int eresting to n ote tha t the ‘ choice ’ of effector res ponse is pr obably determined b y the innat e sensing pa thwa y act i vat ed by a give n chal- lenge—fo r example, PRR sensin g of micr obial P AMPs b y surface epithe - lia alone can ind uce only lo w-cost respo nses; the same PRR activat ed in macro phages o r DCs behind epithelial barriers may in duce res ponses of higher cost; the sensing of pa t hog en in vasivenes s, viability , replicatio n huma ns, Langerha ns cells ind uce the secretion of T H 2 cell cytokines in mixed-leukocyte reactions mor e efficiently than o ther skin DC subsets do 71,72 , which suggests tha t differen t skin D C subsets ma y carry out the priming o f T H 2 cells in mice and h umans ( F ig. 2 ). Recognition by the inn ate imm une system is also critical for an tibody respon ses. T cell - independent B cell re sponses ar e induced by s ignals from both TLRs and B cell a ntigen r ecepto rs (BCRs). B-1a and B-1b cells prod uce nat ural immunoglob ulin M (IgM) a ntibodies that co nfer pro tection again st infection with certain bacteria, such as S trep tococcus pneumonia 90 an d Borrelia herm sii 91 , as well as the early I gM response to viruses such as influenza virus 92 . B-1a cells expre ss TLR9 and TLR7 and re spond rob ustly to their ligands 93 . The BCR induces nonca nonical signaling via the transcription facto r NF- k B that co mplem ents TLR4- induced cano nical signaling via NF- k B in respon se to LPS to induce activation-in duced cytidine deaminase express ion needed for imm u - noglobulin class swi tching 94 . T cell - dependent an tibody response req uires a t least three signals, consis ting of enga gemen t of the BCR by an an tigen, and signals from fol - licular helper T cells (T FH cells) in the fo rm of CD40L (the ligan d for the costimula tory receptor CD40) a nd cytokines that ind uce class swi tch to a particular heavy-chain isotype. In addi tion, T cell - dependen t antibody respon ses are con trolled by the recognition o f B cells by the in t rinsi c innat e immune sys tem. First, co-eng agemen t of BCR with the comp le - ment r ecepto r CD21 determines whether the an tigen has been flagged by the com plement system in the f orm of a ttachment of the co mp lement com ponent C3d . A ttachment of the C3d fragmen t to a protein a ntigen has been shown to su bstantially incr ease the sensitivity of B cells 95 . CD21 then signals through the signal-transduction r eceptor CD19 co mp lex to induce signaling via the kinase PI(3)K tha t co-stimula tes the BCR signaling 96 . Second, ano ther co-recepto r , CD22, determines whether the an tigen bound by BCR con tains a 2,6 sialic acids. Because a 2,6 sialic acid is pr esent on h ost glycocon juga tes bu t not o n most bacterial carbohy - drates 97 , this co-en gagemen t helps to determine the origin of the an tigen. When CD22 is en gaged by i ts sialic acid ligand, i t activat es the lipid p hos - pha tase SHIP , which conv erts phospha tidylinosit ol-(3,4,5)-trisphosph ate (genera ted by PI(3)K) in to phospha tidylinositol-(3,4)-b isphosphat e and thus inhib its down stream st eps in the PI(3)K signaling path way 96 . Finally , an tibody responses, particularly those of I gG2 isotype (mouse) or I gG1 and I gG3 is o types (human), a re r egulated by B ce ll–intrinsic TLRs sig - naling. In this co ntext, TLRs p robab ly function to determine whether the antig en bound by the BCR is a P AMP or is associated with a P AMP . The importance o f TLR signaling in B cells has been demons trated in Cost Order of eng agement IgG1 (mouse) IgG4 (human) PRR and IFN- g –activat ed macrophages PRR- activat ed macrophages Inducible Constitutiv e AMP Mucins Circulatory IgM Secretory IgA Neutrophils IgG2a (mouse) IgG1 (human) IgG2b (mouse) IgG3 (human) T H 1 CTL T H 17 Figure 3 The order of effector function engagement, from lowest cost to highest cost. Defense mechanisms of the immune system have different costs to host fitness. The order of engagement of effector functions corresponds to their increasing costs (here, their potential to cause immunopathology). The low-cost effector mechanisms, such as antimicrobial peptides (AMPs), secretory IgA and circulatory IgM, are expressed constitutively . When they are insufficient to contain pathogens, the response of next lowest cost is induced (here, tissue-resident macrophages); when this response is insufficient, neutrophils are recruited, and so on. The examples of effector responses presented here and their costs are for illustration purposes only; they are neither comprehensive nor quantitative. REVIEW npg © 201 5 Nature America, Inc. All rights reserved. NA TURE IMMUNOL OGY VOLUME 16 NUMBER 4 APRIL 2015 349 2 immune r esponse. Th e differen t modes of recognitio n by the inna te immune sys tem described above opera te in these cell types to induce prod uction of the first level of cytokines. Th e ‘level 1’ cytokines inclu de IL-12, IL-23, IL-6 a nd IL-1 b for the type 1 imm une respo nses, and TSLP , IL-25, IL-33 an d IL-1 a fo r the type 2 immune res ponses 115,116 . These cytokines act on the second cat egory of cells, which is made up o f various populatio ns of l ymphocytes, incl uding ILCs, inna te-like lymphocytes (ILLs; includin g NKT cells, MAIT cells and epi t he lial gd T cells), T FH cells and T RM cells. In respon se to ‘level 1’ cytokines, these lymp ho- cytes produce ‘level 2’ cytokines. These include IFN- g , IL-17, IL-22 f or type 1 immune re sponse, and IL -4, IL-5, IL-9, IL -13 and AREG fo r type 2 immune r esponse. IL -21 prod uced by T FH cells is com mon to both type 1 immune re sponses and type 2 imm une respon ses. The ‘level 2’ cytokines act on the third ca tegory of cells, which ar e effectors of the immune r esponse. These include macr oph ages, neu trop hils, epithelial cells, eosinophils a nd basophils, an d B cells (specifical l y B-2 cells), as well as sensory neuron s, endotheli um and smoo th muscle cells. The se cells perform diverse effector function s, includin g barrier defense, kill - ing and exp u ls ion of pa t h ogens, a ntibody pr oduction, an d tissue repa ir . Some cell types can function both as sensors and as effector s ( Fig. 4 ). Macr ophag es function as sensors when activa ted by the PRRs a nd as effectors when activa ted by ‘level 2’ cytokines p roduced b y lymp hocytes. Ho wever , as disc u ssed above, the r esponses elici ted by these stimuli a re distinct: as sensors, macr ophag es secrete ‘level 1’ cytokines to eli cit respon ses from local lymphocytes. In co ntras t, macrop hages stim u - lated as effecto rs by a ‘level 2’ cytokine (for exa mple , IFN- g ) be co me highly activat ed effectors, ind uce rob ust antimicro bial and p hagocytic respon ses, including the p roduction o f reactive o xygen and ni t r ogen species. Similarly , epithelial cells ser ving as sen sors of he lminth infection prod uce the ‘level 1’ cytokines IL-33, IL-25 an d TSLP , whereas epithelial and virulence activities induce r esponses o f pro gressiv ely higher cost. Thus, ma crop hages activa ted by PRRs alo ne induce effector r esp o nse of lower cos t (secretion of cytokines a nd an timicrobial peptides) than those induced by m acrop hages activa ted by PRRs a nd in terfero n- g (IFN- g ) (enhanced microb icid al activities a nd collat eral damage) ( F ig. 3 ). This strat egy should optimize the im mune r esponse so as to minimize its cos t while pro viding sufficient pr otection. In addition t o immuno pathology , immune r esponses can h ave o ther costs, most no tably metabolic cos ts. Theref ore , immune r esponses ar e probably calib rated o n the basis of weighted co ntribu tion of differ ent costs. Design principle of immune responses Over the past decade, man y exciting di scoveries ha ve been made about the functions and r egulation o f ILCs 108–110 , tissue-residen t memory T cells (T RM cells) 111–114 and epithelial cells, as well as the signals tha t activate these cell types and the cytokines they prod uce. These discov - eries paint a co mpl ex pictur e of m ultiple cell types connected b y cyto - kines that perform dis tinct functions. Ho wever , behind this complexi ty , there is a sim pler pa ttern that r eveals a commo n design principl e of the immune r esponse, wi th man y details being a variatio n on a comm on theme. The commo nalities become a ppar ent with the co nsidera tion that all the cell types invol ved in the initia tion and ex ecution of the imm une respon se fall into three cat egories ( F ig. 4 ). The first cat egory is made up of cell types tha t function as sensors of inf ection or damag e. These are the cell types that exp ress va rious PRRs a nd other sensing mac hin - er y t o detect microorga nisms, macr oparasi tes, al ler gens, to xins and venom s and an y other stimuli that elici t imm une respon ses. The cell types that function as sensors inc lude DCs and macro phag es for the type 1 immune re sponse, and ep ithelial cells and m ast cells fo r the type T ype 1 immunity T ype 2 immunity IL -1 β IL -12 IL -23 IL -6 B cell ILC1 ILC3 T H 1 T H 17 CTL NK NKT γδ T IL -1 α TSLP IL -25 IL -33 IFN- γ IL -17 IL -22 IFN- γ IL -21 IL -4 IL -5 IL -13 AREG IL -9 Macrophage Neut ro phil Epithelia Basophil Eosinophil Macrophage Epithelia Pathogen Le vel 1 cytokine Lev el 2 cytokine Sensor Lymphocyt eE ff ector R esponse ILC2 T H 2 T H 9 NKT Macrophage DC Viruses Bacteria F ungi Pr o to zo a Helminth Allergens V enoms Epithelia T FH 1 Tight junction Antimicrobial peptides Pro lif eratio n B cell IL -4 IL -21 T FH 2 Ly sis of pathogens Wo rm expulsio n Tissue repai r Mucu s secretion IgG 1 (mouse) IgG 2 (mouse) IgG 4 (human) IgG 1 (human) IgG 3 (human) IgG 1 (mouse) IgG 4 (human) IgE Figure 4 The two-tiered design of the immune responses. Immune responses are orchestrated by three categories of cells that function as ‘sensors’ that detect pathogens and secrete ‘level 1’ cytokines, the tissue-resident lymphocytes that respond to ‘level 1’ cytokines to secrete ‘level 2’ cytokines, and the effector cells that respond to ‘level 2’ cytokines to carry out effector functions to eliminate the pathogen. DCs and macrophages serve as sensors for the type 1 immune response and epithelial cells and mast cells for the type 2 immune response. ‘Level 1’ cytokines act on terminally differentiated lymphocytes, including ILCs, ILLs, T FH cells and T RM cells. In response to ‘level 1’ cytokines, these lymphocytes produce ‘level 2’ cytokines. The ‘level 2’ cytokines act on the effector cells of the immune response. These include macrophages, neutrophils, epithelial cells, eosinophils and basophils, B cells as well as sensory neurons, endothelium and smooth muscle cells. These cells perform diverse effector functions, including barrier defenses, killing and expulsion of pathogens, antibody production and tissue repair . REVIEW npg © 201 5 Nature America, Inc. All rights reserved. 350 V OLUME 16 NUMBER 4 APRIL 2015 NA TURE IMMUNOL OGY consis ting of a cytokine of the IL -1 family (IL-1, IL -18 and IL-33) a nd a cytokine that activa ted the kinase Jak an d transcription facto rs of the ST A T family (IL-12, IL-23, IL-6, IL-15, IL -2, IL-7 and TS LP) to induce the secretion of distinct sets of ‘level 2’ cytokines fr om lym phocytes 120 . Macr opha ges and DCs detect pathoge ns through PRRs a nd secrete IL-12, IL-23 an d IL-6. They also sense pathogens thr ough inflamma - somes and r elease IL-1 b an d IL-18. These ‘level 1’ cytokines act on dif - feren t ia ted lymphocytes of both innat e classes and ada ptiv e classes. IL-12 (an activat or of S T A T4), and IL-18 and IL-1 b (a ctivato rs of the ada pto r M yD88) act on ILC1 cells, NK cells, gd T ce lls and memo r y CD4 + T cells and CD8 + T cells in the tissue to secret e IFN- g . IL-1 b (an activat or of M yD88) together with IL-23 o r IL-21 (activators o f ST A T3) to induce ILC3 cells and mem ory T H 17 cells to secrete IL-17 and IL -22 (ref. 121). Similarly , the ‘level 1’ cytokine TSLP (ST A T5 activat or), together wi th IL-33 or IL -1 a (activato rs of MyD88) r eleased from epi thelial cells, act on ILC2 ce lls and T H 2 memo r y cells to secrete IL-5, IL-13 a nd AREG. Signaling via the recepto r for IL -25 induces activa tion of NF - k B and, together with IL-33, in duces the pr oduction of IL -5 and IL-13 b y ILC2 cells 122 . In addition, the same ‘level 1’ cytokines also ind uce secretion of IL-9 from tis sue-residen t T H 9 memory cells. Of note, secretion of IL -4 is induced onl y upon the engag emen t of T cell an tigen recep tors (T CRs) on me mory T H 2 cells 123 or the treatmen t of ILC2 ce lls with the phorbol ester PMA an d iono my cin 124 and, unlike o ther T H 2 cytokines, comb ina - tions o f ‘level 1’ cytokines are no t suf ficien t to induce IL -4 secretion 120 . ‘Level 1’ cytokines can also pr ogram an tibody responses thro ugh their ac tion on T FH cells. IL-12 ind uces T FH cells to secrete IFN- g 125 , while an as-yet-unknown signal ind uces the secretion of IL -4 from T FH cells ( Fig. 4 ). In mice, T FH cells that secrete IL -21 drive I gG1 respo nses, whereas IL-4-secreting and IFN- g -secreting T FH cells drive I gE responses and IgG2 r esp o nses, res pectively 126 . cells respon ding to the ‘level 2’ cytokine IL-13 become activa ted and differen tiate in to goblet cells to incr e ase m uc us secr etion. The r eason the same cell types can function as both sensors an d effectors pr esum - ably r eflects their evolutiona r y h istory when they operated in sim pler path ways, performin g both sensing functions and e ffector functions withou t the inv olvemen t of lymphocytes. There a re some varia tions o n the commo n theme of two-tier ed design of the imm une response. F or examp le, in some cases, the s ingle-tiered cytokine system co nsists o f s en sor cell types that media te direct effector respon se through secretion of ‘leve l 1’ signals ( Fig. 5 ). Fo r anti viral pro - grams, plasmacyto id DCs ser ve as a key sensor f or the detection viruses through endosomal TLRs t o produce a b urst o f type 1 interfer ons, which act systemically to block viral rep lication 117 . Infected cells t hemselves prod uce type 1 interfer ons to m ediate similar effects locally . Similarly , mast cells tha t reside in the m ucosa sense the presence o f the noxio us substances a nd parasitic w orms, and r eleas e his tamines and p rostaglan - dins, which act o n local vasculature t o induce vasodilatio n and leakag e, and act on in testinal and air wa y smooth muscles to induce peristalsis, con traction and expulsio n of parasi tes. Histamine p roduced by m ast cells and TSLP p roduced by ep ithelial cells can also stim ulate a subset of C-fiber neuron s to induce the i tchin g sensation, which he lps rid of macroparasi tes and ectoparasites 118 . The sin gle-tiered design pr obably reflects a more evol utiona rily ancien t strat egy in w hic h the sensor and effector functions wer e carried out b y the same cells. Suc h a strategy may hav e been optimal in inv ertebra te deuter ostomes that ha ve numero us PRRs bu t have lim ited cell types 119 . The two-tiered design uses ILCs, ILLs a nd T RM cells to media te the effector respo nses. U nli k e secretion by IL Cs or ILLs, the secretion o f ‘level 2’ cytokines by T RM cells u sually requir es specific antigen, altho ugh not necessari ly 120 . The ‘leve l 1’ cytokines usually work in co mbin ation s T ype 1 immunity T ype 2 immunity Histamine Pr ostaglandins Pr oteases Infect ed cells Endothelia Smooth muscle Neurons P athogen Lev el 1 signal Sensor L ymphocyt eR esponse Ef fector Helminth Allergens V enoms Mast cell Viruses pDC CTL Ce ll death Worm and allergen e xpulsion T ype I inter fe rons Enhanced barrier function Figure 5 Single-tiered immune responses. Some immune responses involve only the ‘level 1’ signals that act directly on the effector cells. For antiviral responses, plasmacytoid DCs serve as a key sensor for the detection of viruses through endosomal TLRs to induce type 1 interferons, which block viral replication. 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This is a reflection of the clonal distrib ution o f their TCRs and the r equiremen t for extra steps of pro lifera tion and differ entia tion befor e they can become com petent to function as cells denoted as the l ymphocyte cat egory . In con t ras t, ILCs that lack T CRs, ILLs that ha ve in varian t TCRs, and T RM cells that have man y feat ures in co mmon wi th ILCs and ILLs, either do n ot need to undergo p rolif eratio n and differen ti a tion steps (ILCs and ILLs), o r hav e already don e so in the past (T RM cells). Future perspectives The focus of this Review has been the emerging princip les of recogni tion by the inna te immune system a nd con t r ol o f adap tive imm unity . Futur e discoveries will no doub t lead to additio nal revisions a nd modifica - tions o f the current paradigm s. Some exciting e merging new direction s include the sensin g path ways o f the immun e system that d etect specific dietary and microbial metaboli tes, incl uding short-cha in fat ty acids and vit amins 127–129 . In additio n, the detection of bacterial pigmen ts by the ary l h ydrocarbon recepto r has been found t o regulat e an an tibacte - ri al res ponse 130 . The sensin g of xen obio tic substances b y this recepto r has been found to ha ve a role in the enhancemen t of barrier immunity through IL-22 p roduction a nd other mecha nisms 131 . Ano ther sensor of xenob iotic substan ces, PXR, has been found to con t r ol in testinal inflam - matio n by sensing bacterial metabolit es 132 . H ow all these path ways fit in with the curren t models o f immun e recognitio n is an ex citing a rea of fut ure in vestiga tion. In addi tion to expandin g the knowledge of sensin g path ways o f the innat e immune sys tem, a ma jor challenge f or the fut ure studie s is to define the rules of engagemen t t h at determine the function s of these path ways in the co ntext o f infectious diseases. This will be essential for ad vancing the ab i li ty to design effective vaccines. A ma jor h urdle in this area has been the lack of und erstanding o f the requir emen ts for the induction o f pro tective imm unity . Instead, imm unogenici ty is often used as a surroga te for pr otective im muni ty in vaccine desi gn and trials. Ho wever , immunogenici ty , a pr operty related t o the ability to in duce an immune r esponse, is n ot equivalen t to protective imm unity , which is conferr ed by imm une respo nses able to elimin ate the pa thogen witho ut killing the host in the process. The im munog enicity of vaccin es often leads to pr otective imm unity when the la tter is based on neu tralizing an tibodies. In most other cases, vaccines tha t are im munog enic often do not pr ovide prot ection. A given imm une respon se may or m ay no t be pro tective fo r an y one o f several reasons; it co uld be of wro ng specificity , effector class, loca tion, magni tude o r dura tion. Th us, just as the rules of imm unogenici ty have been defined ov er the past 15 years, a ma j o r challenge fo r the futur e will be to define the r ules o f pr otective imm unity . ACKN OWLEDGMENTS W e t h ank Y . K umamot o for hel p with Ta b l e 1 . Sup ported by the US Na t io nal Insti tutes o f Health (AI081884, AI062428 a nd AI064705 to A.I., and AI046688, AI089771 and DK071754 to R.M.), Else Krö ner-F resenius-S tiftung (R.M.) and the Ho ward H ughes Medical Insti tute (A.I. a nd R.M.). COMPETING FIN ANCI AL INTERESTS The au thors declar e no com peting financial interes ts. Reprints and permissions information is available online at http://www .nature.com/ reprints/index.html . 1. Janeway , C.A. Jr . 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