Immunology Chapter 5: Cell-Mediated Immune Responses
Cell-mediated immunity uses T cells to fight intracellular microbes
2 ways a microbe can infect and hang out in infected cells:
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It resists phagocytes, and then uses the phagocyte to live in
o Only part of a phagocyte that kills the pathogen is the vesicle, so if they escape the
vesicle, they’re safe in the phagocyte
Binding to, and then infecting, host cells
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Naïve T cells constantly circulate through the lymph organs, searching for foreign protein antigens
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Have antigen receptors to recognize the foreign stuff, but can’t do anything about it until the T
cell is activated
The job of naïve T cells is to recognize foreign antigens
Antigen recognition actives the T cell, causing it to differentiate into effector cells
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Microbe protein antigens are taken to the lymph organs by antigen presenting cells (APCs), and
are expressed on the phagocyte MHC, to show to the T cells
When a T cell recognizes an antigen, the T cell stops and activates
o So T cells first encounter antigens in the peripheral lymph organs
At the same time as the T cells are recognizing the antigen, the APC and other innate
mechanisms provide signals to the T cell
Once activated, the T cell releases cytokines
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The cytokines can trigger proliferation of antigen-specific T cells, which is called clonal expansion
Some of the cells that proliferate will then differentiate into effector T cells, whose job is to get
rid of the microbe
Some of the effector T cells will work with B cells in the lymph organ to get rid of the microbe
there, while other T cells will go into circulation to the site of infection to get rid of the microbe
there
Some of the cells that proliferate will instead differentiate into memory T cells, which are
inactive on this exposure, but stick around ready to quickly respond to the next exposure
Once the infection is eradicated, the stimuli for the T cells to proliferate ends, and T cell levels go back to
normal
T cell antigen recognition:
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Types of T cell receptors:
o TCR – recognizes MHC associated peptide antigens
o CD4/CD8 coreceptors- recognize MHC molecules
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o Adhesion molecules- bind T cells to APCs
o Receptors for costimulators from APCs
o Accessory molecules- complementary molecules that work in signaling and adhesion
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The TCR and the CD4/CD8 coreceptors all work together to recognize MHC complex with its
peptide antigens
o Binding to these receptors is the first signal that initiates T cell activation
o MHC I’s display antigens from the cytoplasm
o MHC II’s display antigens that were taken from the ECF into their vesicles
o The TCR is made of an α chain and a β chain, and both work in antigen recognition
o The TCR can recognize both the displayed antigen peptide, and parts of the MHC
molecule
o The CD4 and CD8 coreceptors help the TCR while it’s binding the peptide-MHC complex,
by binding whatever MHC it is (1 or 2) at a different site
 CD4+ T cells (TH cells) recognize MHC 2 molecules
 CD8+ T cells (TC cells) recognize MHC 1 molecules
o It takes binding of multiple TCRs and CD4/8 coreceptors to activate the T cell
o Binding also must last for a little while to generate enough of a signal for a response
from the T cell
o Once all of this happens, the T cell begins its activation program
In lymphocytes, some molecules are used for antigen recognition, and others are used for
signaling
o Ex: TCR can bind antigens, but can’t signal to the interior of the cell
 The signaling is done by a CD3, and a ῐ chain, which both connect to the TCR to
form the TCR complex
 The TCR α and β chains do the recognizing, and the CD3 and ῐ chain do
the signaling
Adhesion molecules on T cells recognize their ligands on APCs, and stabilize binding of the T cell
to the APC
o Most TCRs bind the peptide-MHC complex with low affinity
o So the adhesion molecules are what are used to keep the T cell bound long enough to
the APC for activation
o The major integrin used is LFA-1, which binds to ICAM-1 on the APC
o In a naïve T cell, the LFA-1 is in a low affinity state
 Cytokines from innate immunity convert the T cell’s LFA-1’s to a high affinity
state, and the LFA-1’s cluster together
 Antigen recognition also increases the affinity of the T cell’s LFA-1’s
The full activation of T cells is dependent on the recognition of costimulators on the APC’s
o This stimuli works with the stimulation from the antigen
o 2 costimulators of APCs used for T cells are B7-1 (CD80) and B7-2 (CD86)
 Expression of these is greatly increased when the APC sees a microbe
 The receptor on T cells for B7-1 and -2 is CD28
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Without CD28-B7 binding, binding of the TCR alone can’t active the T cell
 Things that block this binding are used to treat rheumatoid arthritis
o Costimulation guarantees that only a microbe, and not a harmless foreign substance,
will activate the T cell
o CD40 on the APC is another costimulator that binds the CD40 ligand on the T cell
 For this one, T cells express the CD40 ligand to bind the APC CD40, in order to
make the APC express more B7 costimulator, and secrete cytokines like Il-12,
which enhances T cell differentiation
Substances that activate the APCs are necessary for a vaccine to work, they’re called adjuvants
o Adjuvants work by causing expression of costimulators on APCs, and stimulating APCs to
secrete cytokines like Il-12 that activate T cells
o Adjuvants are usually products of dead microbes, that will mimic the microbe
Other receptors in the CD28 family can inhibit T cells
o CTLA-4 – recognizes B7 on APCs
o PD-1 – recognizes ligands of many cells
o Both are induced in T cell activation, and lack of these may cause autoimmunity
The activation of CD8+ T cells is stimulated by MHC I’s, costimulators, and TH cells
o CD8+ T cells have a few differences in their responses
 One difference is that the cytoplasmic antigen of the virus-infected cell has to
be cross presented by dendritic cells
 Another difference is that CD8+ T cell differentiation into TC cells may need TH
cells
 The same APC will also present MHC 2 for activating the TH cells
 The TH cell can release cytokines to activate CD8+ cells
o HIV targets TH cells, preventing activation of TC cells
Activation of T cells
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Once recognition has finished, T cells express proteins involved in the proliferation,
differentiation, and effector function of the cell
Gene transcription and protein synthesis increase quickly after recognition
TCR’s and co-receptors cluster and cross-link when they bind MHC-antigen complexes
After binding, the TCR, CD4/8 co-receptors, and CD28 cluster at the center of the T cell
membrane, and the integrins form a ring around the cluster
o Creates an optimal arrangement for inducing activating signals in the T cell
o The T cell – APC cell connection is called an immunologic synapse
o The clustering of CD4 and CD8 activate a tyrosine kinase called Lck at their tails
 Lck then phosphorylates tyrosine ITAMs on the CD3 and ῐ chain of the TCR
 Once phosphorylated, ITAMS bind another tyrosine kinase called ZAP-70
 ZAP-70 then also gets phosphorylated by Lck, activating the ZAP-70, which then
goes and phosphorylates other proteins and enzymes in several pathways
 Calcium-NFAT pathway
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 Ras-MAP kinase pathway
 PKC-NF-kB pathway
 PI-3 pathway
Calcium-NFAT pathway
 Initiated when ZAP-70 phosphorylates and activates phospholipase Cγ (PLCγ)
 PLCγ the converts phosphatidylinositol-4,5-bisphosphate into IP3 and DAG
 Inositol 1,4,5-triphosphate (IP3) stimulates release of calcium from the ER,
raising the cytoplasmic calcium concentration
 This triggers calcium channels to open and calcium influx occurs
 The calcium binds calmodulin, and the two activate a phosphatase called
calcineurin
 Calcineurin removes phosphates from the transcription factor NFAT in the
cytoplasm
 Once dephosphorylated, NFAT goes to the nucleus to promote genes for the T
cell growth factor called Il-2
 Cyclosporine is an immunosuppressant that works by binding and
inhibiting calcineurin
Ras/Rac-MAP kinase pathway
 ZAP-70 and clustering both recruit Ras and Rac, and activates them by trading
bound GDP for GTP
 Ras or Rac bound GTP activate MAP kinases
 The MAP kinases in this pathway are ERK and JNK
 ERK and JNK promote proteins c-Fos and c-Jun, which combine to form
activating protein 1 (AP-1), which enhances transcription of T cell genes
PKCθ-NF-kB pathway
 PLCγ makes diacylglycerol (DAG), which activates the θ isoform of protein kinase
C (PKC)
 Protein kinase C then activates NF-kB
 NF-kB is initially bound by inhibitor IkB in the cytoplasm of the T cell
 TCR signals lead to activating of a kinase to target IkB for destruction,
releasing NF-kB to go to the nucleus and promote transcription of genes
Phosphatidylinositol-3 (PI-3) pathway
 PI-3 phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) into PIP3
 PIP3 activates the serine-threonine kinase Akt, which prevents apoptosis and
keeps the T cell alive
 This pathway is triggered by TCR, as well as CD28 and Il-2
All of these pathways lead to transcription factors that cause the making of cytokines,
cytokine receptors, and effector molecules
Response of T cells to antigens
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Recognition and signaling lead to a response by T cells involving proliferation and differentiation
into effectors
Cytokines are proteins that function as mediators of immunity and inflammation
o In adaptive immunity, cytokines are released by T cells
o Interleukin means a protein that’s made by leukocytes, and acts on leukocytes
o The first cytokine made by a CD4+ T cell within 1-2 hours of activation, is Il-2
 Activation also increases the ability of the T cell to respond to Il-2
 Normally, the T cell only has 2 of the 3 chains of its receptor for Il-2
 Once activated, the T cell makes the 3rd chain in order to bind Il-2
 Il-2 stimulates survival and proliferation of T cells, so it’s aka T cell growth
factor
 Il-2 stimulates T cells to enter the cell cycle and divide, increasing the
number of antigen specific T cells
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Within 1-2 days of activation, T cells start to proliferate
Proliferation allows the immune response to keep up with the proliferation of the microbe
The progeny of the proliferating T cells then differentiate into effector cells and memory cells
o Effector cells appear within 3-4 days after exposure
 The effectors then leave the lymph organ and go to the site of infection to kill
the microbe
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o CD4 TH cells can differentiate into effector cells that respond to the antigen by making
surface molecules and cytokines that will activate phagocytes and B cells
 The most important surface protein in a CD4+ effector function is CD40 ligand,
which binds to the CD40 of phagocytes and B cells, activating them
 CD40 binding causes the expression of costimulators on the APCs, and
also causes them to make T cell activating cytokines, causing positive
feedback for T cell activation
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 CD4 TH cells can also differentiate into effector cells that make cytokines
 3 types: type 1 TH (TH1), type 2 TH (TH2), and TH17
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 TH1 cells stimulate phagocytes to eat and kill microbes
o TH1 cells make interferon-γ (IFN-γ), which activates macrophage
to kill microbes, called classical pathway of macrophage ‘s
activation
o IFN-γ also stimulates making of antibodies that promote
phagocytosis of microbes by binding to both the phagocyte and
complement
o IFN-γ can also stimulate expression of MHC-2’s, and B-7’s
 TH2 cells recruit eosinophils to come get parasites
o TH2 cells make Il-4, 5, and 13
 Il-4 stimulates making of IgE antibodies
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 IgE activates mast cells, and binds to eosinophils
 Il-5 activates eosinophils
 Il-4 and Il-13 stimulate expulsion of parasites from
mucosal organs, and inhibit microbe entry by
stimulating mucus secretion
 Called “barrier” immunity
 These cytokines also stimulate macrophage to repair,
called the alternative pathway of macrophage
activation
 These cytokines can also inhibit the TH1 cytokines
 TH17 cells make Il-17 and Il-22 to mediate inflammation
 Differentiation into the specific kinds of TH depends on the stimuli the
cell receives when it meets microbial antigens
o When T cells are exposed to Il-12 from phagocytes, and IFN-γ
from NK cells, it differentiates into a TH1 cell
 Example of innate immunity influencing adaptive
o Il-4 tells T cells to form TH2 cells, but we don’t know where the
Il-4 comes from
o Inflammatory cytokines from phagocytes like Il-1, 6, 23, and
TGF-β, tell T cells to form TH17 cells
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CD8 T cells activated by antigens and costimulators differentiate into TC cells that kill
infected cells
 Make stuff that drill holes in the cell, and then make other stuff that go in and
cause apoptosis
Other T cells differentiate into memory T cells
 Need signals from cytokines like Il-17 to stay alive
When the infection is gone, all these signals that were keeping the extra T cells alive are gone, so the T
cells die by apoptosis