Transcript II. T cell activation

Jianzhong Chen, Ph.D.
Institute of Immunology, ZJU
 Concept of immune response
 T cell-mediated immune response
 B cell-mediated immune response
I. Concept of immune response
 A collective and coordinated response to
the introduction of foreign substances in an
individual mediated by the cells and
molecules in the immune system.
II. T cell-mediated immune response
 Cell-mediated immunity is the arm of the
adaptive immune response whose role is to
combat infection of intracellular pathogens,
such as intracellular bacteria (mycobacteria,
listeria monocytogens), viruses, protozoa,
etc.
Types of intracellular microbes combated by T cellmediated immunity
1. Phases of T cell responses
 The response of T cells to antigens consist of a
series of sequential steps that result in an
increase in the number of antigen-specific T
cells and the conversion of naïve T cells to
effector T cells.
Three phases
 Antigen recognition phase
 Activation and differentiation phase
 Effector phase
2. Antigen recognition
1) Substances that induce T cell activation
 antigen (presented by APC)
 Superantigen
 mitogen (PHA, ConA, etc.)
 mAb (anti-T cell surface molecules)
2) Double signals for T cell activation
 The first signal
TCR-antigen peptide-MHC (double recognition)
CD4-MHC II or CD8-MHC I
 The second signal (co-stimulatory signal)
Interactions between co-stimulatory molecules
on APC and corresponding receptors on T cells
CD28/CTLA-4 —B7, LFA-1—ICAM-1,
LFA-2—LFA-3
Ligand-receptor pairs involved in T cell activation
Important properties of the major accessory molecules
The role of costimulation in T cell activation (A)
Anergic T cell
The role of costimulation in T cell activation (B)
3. Signal transduction in T cell activation
 On recognition of Ag and costimulators, T
cells express proteins that are involved in
proliferation, differentiation and effector
functions of the cells.
 The biochemical pathways that link Ag
recognition with T cell responses consist
of the activation of the enzymes,
recruitment of adapter proteins, and
production of active transcription factors.
There two major signaling pathways
1) PLC-
TCR-CD3→ITAM → ZAP-70→LAT, SLP-76→ PLC-
IP3 → Ca2+ →calcineurin → NFAT
→PIP2{
DAG→ PKC → NF-B
2) MAPK
ZAP-70→phosphorylation of LAT and SLP-76→Grb-2 and
Sos→Ras→MAPKK→MAPK→AP-1
Target genes activated by transcription factors
CKs and their receptors
CAMs
MHC
PIP2
Signal transduction pathways in T cell activation
gene expression of T cell
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cytokine gene expression
cytokine receptor gene expression
adhesion molecule gene expression
MHC
4. Proliferation and differentiation of T cells
1) CD4+ T cells: Th, Tr, Tm
regulated by cytokines
2) CD8+ T cells: Tc
Th-dependent
Th-independent: virus infected DC that
highly express co-stimulatory
molecules can directly stimulate CD8+
T cells.
Activation of CD8+ T cells
• Cytokines are required in T cell
proliferation and differentiation
Activated T cells can produce cytokines (IL-2,
4, 7, 10, etc.) and express cytokine receptors,
that promote T cells to proliferate and
differentiate.
5. Effector functions of activated T cells
1) CD4+ T cells
Th1: secrete IFN-, etc.
Activate macrophages
express CD40L
express FasL, kill Fas+ target cells
effect on lymphocytes: IL-2
effect on neutrophil: TNF-,
Th2: promote B cell growth and Ig production
mediate hypersensitivity
activated Th1 cell
IFN-γand CD40L
FasL or TGF-β
Lumen of blood vessel
chemoattractive
exudation
Infected site
activate Mφ to
kill phagocyted
bacterias
kill infected cell
and released
bacterias were
killed by Mφ
induce T cell
proliferation
induce
differentiation
of bone
marrow Mφ
Induce
Mφexudation
by endothelial
cell activation
Biological roles of Th1 cell secreted cytokines
recruitment of
Mφto local
infected site
Function of Th2 CD4＋T cell
Regulate Mφ(recruitment, inhibition：IL-10/FasL/TGF-)
B cell activation, Ig isotype switching
2) CD8+ T cells
Cytotoxicity: kill target cells
a. necrosis: perforin and granzyme
b. apoptosis: granzyme, FasL
Characteristics of CD8+ T cell cytotoxicity
a. Specificity
b. MHC I restriction
c. High efficiency
Mechanisms of
killing of infected
cells by CD8+ CTLs
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© 2005 Elsevier
Two types of cell-mediated immunity
Cell-mediated immunity against intracellular microbes
T cell mediated immune response and
immune effects
• antigen：
• cell：
• effect agent：
• immune effects:
TD-Ag
T cell and APC
Th/CTL（Tc）
anti-intracellular infection
anti-tumor
immunological injury
delayed type hypersencitivity, DTH
graft exclusion reaction
autoimmune disease
6. Generation of memory T cells
1) CD45RA-CD45RO+,
2) Long-lived memory to specific antigen
3) Mediate faster, stronger and more
effective immune response
4) Mechanism: remains elusive
7. Activation induced cell death, AICD
1) Activation induced cell death
Activated T cells express FasL that
induce apoptosis of Fas positive T cells.
2) Passive cell apoptosis
Ag, survival signals and growth factors 
proliferation
Persistent
stimulation
Deprived of
growth factors
mitochondria
cytochrome C
Activation induced cell death
Passive cell death
Two mechanisms of lymphocyte apoptosis