How the Immune System Works
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How the Immune System Works


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the Th2 cytokine profile, there will be plenty of IL­4 
around \u2013 because this is one of the cytokines Th2 cells 
secrete. However, the initial source of IL­4 required for 
Th2 commitment has not yet been identified.
The second interesting point is that Th2 cells produce 
cytokines (IL­4 and IL­5) which can influence B cells to 
helper T cell, that Th cell will be instructed to become a 
helper T cell which produces the \u201cclassical\u201d Th1 cytokines: 
TNF, IFN­\u3b3, and IL­2.
Why these particular cytokines? Let\u2019s see what these 
cytokines do. The TNF secreted by Th1 helper T cells 
helps activate macrophages and natural killer cells. 
However, macrophages only stay activated for a limited 
time. They are lazy fellows which like to go back to 
\u201cresting and garbage collecting.\u201d Fortunately, the IFN­\u3b3 
produced by Th1 cells acts as a \u201cprod\u201d that keeps macro­
phages fired up and engaged in the battle. IFN­\u3b3 also 
influences B cells during class switching to produce 
human IgG3 antibodies. These antibodies are especially 
good at opsonizing viruses and bacteria and at fixing 
complement.
NK cells can kill three or four target cells in about 16 
hours, but then they \u201ctire out.\u201d The IL­2 produced by Th1 
cells can \u201crecharge\u201d NK cells, enabling them to kill some 
more. In addition, IL­2 is a growth factor which stimu­
lates the proliferation of CTLs, NK cells, and Th1 cells 
themselves, so that more of these important weapons will 
be available to deal with the attack.
Altogether, the Th1 cytokines are the perfect package 
to help defend against a viral or bacterial attack in the 
tissues. The Th1 cytokines instruct the innate and adap-
tive systems to produce cells and antibodies that are 
especially effective against these invaders, and keep the 
warriors of the immune system fired up until the invad-
ers have been defeated.
Th2 HELPER T CELLS
Now suppose that you have been infected by a parasite 
(e.g., hookworms) or you have eaten some food that is 
contaminated with pathogenic bacteria. In the tissues that 
line your intestines, a battle will be raging. Dendritic cells 
DC Th1
Cell
TCR
Antigen
Class II 
MHC
Molecule
IFN-\u3b3
TNF
IL-2
IL-12
DC Th2
Cell
TCR
Antigen
Class II 
MHC
Molecule
IL-5
IL-4
IL-4
IL-13
64 LECTURE 6 T Cells at Work
IL­21 is a growth factor for Th17 cells, so once these 
helper T cells have committed to being Th17 cells, they 
stimulate themselves and other Th17 cells to proliferate. 
This increases the number of cells which can battle the 
fungus. Secretion of the \u201csignature cytokine,\u201d IL­17, 
results in the recruitment of massive numbers of neu­
trophils to the site of infection. These neutrophils help 
defend against pathogens against which Th1 and Th2 
cells are relatively ineffective, including fungi and some 
extracellular bacteria \u2013 bacteria which do not enter cells. 
Indeed, patients who have a genetic defect in IL­17 secre­
tion suffer from devastating fungal infections (e.g., infec­
tion with the common yeast, Candida albicans) even though 
their Th1 and Th2 helper T cells function normally. Finally, 
IL­17 and IL­21 influence B cells to produce antibody 
classes which can opsonize fungi or bacteria and can acti­
vate the complement system. So if you are attacked by 
fungi or extracellular bacteria, the cytokines secreted by 
Th17 cells are there to help protect you.
Th0 HELPER T CELLS
Some helper T cells (the so­called \u201cTh0\u201d cells) remain 
\u201cunbiased\u201d when they first are activated, retaining the 
ability to produce a wide range of cytokines. It appears 
that DCs tell these helper T cells where to go, but not what 
to do. However, once Th0 cells reach the battle scene, the 
cytokine environment they encounter there causes them 
to commit to the cytokine profile required for the defense. 
For example, when Th0 cells exit the blood to fight a 
bacterial infection in the tissues, they encounter an envi­
ronment rich in IL­12. This is because Th1 cells that are 
already fighting the bacteria there produce IFN­\u3b3. This 
cytokine, together with danger signals like the bacterial 
molecule LPS, activates tissue macrophages, which 
make either IgE antibodies (to defend against parasites) 
or IgA antibodies (to defend against pathogenic bacteria). 
However, it would be unusual for a person to be infected 
with parasites and pathogenic bacteria simultaneously. 
Consequently, you wouldn\u2019t want Th2 cells to influence 
B cells to make both IgE and IgA antibodies. That would 
be wasteful (and probably dangerous). So how does a Th2 
cell decide whether to instruct B cells to make IgE or IgA 
antibodies?
Immunologist don\u2019t have a complete answer to this 
question, but a major factor in this decision is the location 
from which the dendritic cells are dispatched. I men­
tioned earlier that DCs have a \u201cregional identity.\u201d For 
example, there are dendritic cells which reside in \u201cPeyer\u2019s 
patches\u201d \u2013 special areas of the intestine that are important 
in defending against pathogenic bacteria which have 
been ingested. These particular dendritic cells are 
\u201cimprinted\u201d by the environment of the Peyer\u2019s patch to 
deliver signals (e.g., via co­stimulatory molecules) to Th 
cells which cause them to assist with IgA antibody pro­
duction. On the other hand, dendritic cells which are 
stationed beneath areas of the intestine that are suscepti­
ble to invasion by parasites are imprinted so that they 
convey signals to Th cells which bias them to help B cells 
produce IgE antibodies. That\u2019s the basic idea, but the 
details have yet to be worked out.
Th17 HELPER T CELLS
The existence of helper T cells which produce the Th17 
cytokine profile is a recent discovery, and less is known 
about Th17 cells than about Th1 and Th2 helper T cells. 
One reason for this is that Th17 cells function, at least in 
part, in the defense against fungi \u2013 and the immune sys­
tem\u2019s response to a fungal attack is not nearly so well 
researched as the immune defense against bacteria and 
viruses. Consequently, the story on Th17 cells is far from 
complete, but here is the emerging picture.
If a dendritic cell is stationed in an area of the body 
which is being attacked by fungi (e.g., a vaginal yeast 
infection) or certain extracellular bacteria, that DC will 
travel to a nearby lymph node and activate those 
helper T cells which recognize the antigens the DC is 
presenting. These traveling dendritic cells will produce 
TGF\u3b2 and IL­6, which together with co­stimulatory mol­
ecules, influence newly activated helper T cells to produce 
the Th17 subset of cytokines, which includes IL­17 and 
IL­21.
DC Th17
Cell
TCR
Antigen
Class II 
MHC
Molecule
IL-17
IL-21
IL-6
TGF\u3b2
LECTURE 6 T Cells at Work 65
by cellular receptors or are degraded. Consequently, 
when we talk about helper T cells being biased toward 
secreting a certain cytokine profile, we are talking about 
something very local. Clearly, you wouldn\u2019t want every 
Th cell in your body to be of the Th1 type, because then 
you\u2019d have no way to defend against a respiratory infec­
tion. Conversely, you wouldn\u2019t want to have only Th2 
cells, because the IgA or IgE antibodies made in response 
to the Th2 cytokines would be useless if you get a bacte­
rial infection in your big toe. In fact, it is the local nature 
of cytokine signaling which gives the immune system 
the flexibility to simultaneously mount defenses against 
many different invaders that threaten different parts of 
the body.
It is also important to note that dendritic cells are 
members of the innate system team. Consequently, the 
innate immune system not only informs the adaptive 
system when there is danger, but the innate system also 
\u201ccoaches\u201d the adaptive system to insure that the appro-
priate weapons are sent to the right places.
SUMMARY
To summarize, dendritic cells are stationed beneath all 
exposed surfaces, where they wait for information on 
the identity of invaders which breach the barrier 
defenses. This information is collected by receptors that 
recognize either