T-Cell Activation • 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.

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Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi
T-Cell Activation
• 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 cell-mediated 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.

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Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi
Three phases
• Antigen recognition phase
• Activation and differentiation phase
• Effector phase

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Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi
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. 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
▪ CTLA4 or CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), also known as
CD152 (cluster of differentiation 152), is a protein receptor that, functioning as an

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Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi
immune checkpoint, downregulates the immune system. CTLA4 is found on the surface
of T cells, and acts as an "off" switch when bound to CD80 or CD86 on the surface of
antigen-presenting cells.
▪ Lymphocyte function-associated antigen 1, also known as LFA-1 is found on all T-cells
and also on B-cells, macrophages and neutrophils and is involved in recruitment to the
site of infection. It binds to ICAM-1 on antigen-presenting cells and functions as an
adhesion molecule.
▪ VLA-4 (Very Late Antigen-4) is an integrin dimer.
▪ ICAM-1 (Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of
Differentiation 54) is a protein that in humans is encoded by the ICAM1 gene.
▪ Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1
(VCAM-1) or cluster of differentiation 106 (CD106) is a protein that in humans is
encoded by the VCAM1 gene. VCAM-1 functions as a cell adhesion molecule.
Important properties of the major accessory molecules

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Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi
The role of costimulation in T cell activation (A)
The role of costimulation in T cell activation (B)

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Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi
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.
Transduction of signals by the TcR
The cytoplasmic domains of the CD3 complex contain 10
Immunoreceptor Tyrosine -based Activation Motifs (ITAMS) - 2
tyrosine residues separated by 9-12 amino acids - YXX[L/V]X6-
9YXX[L/V].
As with B cell receptors, immunoreceptor tyrosine-based activation
motifs (ITAMs) are involved in the transmission of the signals from
the receptor and require clustering of TcR/CD3 and the CD4 or
CD8 co-receptors
Phosphorylation by Src kinases
• Phosphorylation changes the properties of a protein, by
changing its conformation
• Changes in conformation can activate or inhibit a biochemical activity, or create a
binding site for other proteins
• Phosphorylation is rapid and requires no protein synthesis or degradation to change the
biochemical activity of a target
protein
• It is reversible via the action of
phosphatases that remove
phosphate.

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Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi

8. 8
Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi
Tyrosine-protein kinase CSK also known as C-terminal Src kinase is an enzyme that, in humans,
is encoded by the CSK gene. This enzyme phosphorylates tyrosine residues located in the C-
terminal end of Src-family kinases (SFKs) including SRC, HCK, FYN, LCK, LYN and YES1

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Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi
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 mitogen activated protein kinase
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 (Cyclin-dependent kinase)
CAMs (Cell adhesion molecules)
MHC
▪ Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids
just before the phosphate group.
▪ An immunoreceptor tyrosine-based activation motif (ITAM) is a conserved sequence of four
amino acids that is repeated twice in the cytoplasmic tails of certain cell surface proteins of
the immune system. they are found in the tails of important cell signaling molecules such as
the CD3 and ζ-chains of the T cell receptor complex, the CD79-alpha and -beta chains of the
B cell receptor complex, and certain Fc receptors.
▪ ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the
surface membrane of T cells and natural killer cells.
▪ The Linker for Activation of T cells (LAT) and is phosphorylated by ZAP70/Syk protein
tyrosine kinases following activation of the T-cell antigen receptor (TCR) signal transduction
pathway.
▪ Lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa), also
known as LCP2 or SLP-76.
▪ Inositol trisphosphate (IP3), together with diacylglycerol (DAG), is a secondary messenger
molecule used in signal transduction and lipid signaling in biological cells. IP3's main
functions are to mobilize Ca2+ from storage organelles and to regulate cell proliferation and
other cellular reactions that require free calcium.
▪ Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein
phosphatase. It activates the T cells of the immune system and can be blocked by drugs.
▪ Calcineurin activates nuclear factor of activated T cell, cytoplasmic (NFATc), a transcription
factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus,
where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the
growth and differentiation of T cell response.
▪ The Linker for Activation of T cells (LAT) and is phosphorylated by ZAP70/Syk protein
tyrosine kinases following activation of the T-cell antigen receptor (TCR) signal transduction
pathway.

10. 10
Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi
▪ Lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa), also
known as LCP2 or SLP-76.
Signal transduction pathways in T cell activation
gene expression of T cell
• 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

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Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi
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 Activated Th1 cell
1) CD4+
T cells
Th1: secrete IFN-, etc.
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

12. 12
Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi
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
MechanismsofkillingofinfectedcellsbyCD8+CTLs

13. 13
Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi
T cell mediated immune response and immune effects
• antigen： TD-Ag
• cell： T cell APC
• effect agent： Th/CTL（Tc）
• immune effects: 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


14. 14
Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 3: T-Cell Activation
Date: 24th
October, 2019
Made by Amjad Khan Afridi