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Activation of T Cells

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Iqra fiaz
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58 views20 pages

Activation of T Cells

Uploaded by

Iqra fiaz
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Activation of T cells

Activation of T cells
• T cells belong to a group of white blood cells known as lymphocytes

• Play central role in cell-mediated immunity

• Activation of T cells is the central event in the generation of both


humoral and cell-mediated immune responses

• initiated by the interaction of TCR-CD3 complex with a processed


antigenic peptide bound to either a class I or class II MHC molecules
on surface of APCs

• initiates a cascade of events that induces resting T cell to enter the


cell cycle, proliferation and differentiation into memory cells and
effector cells
Development of T cells
• earliest thymocytes express neither CD4 nor CD8, and are therefore classed as double-
negative (CD4-CD8-) cells

• As they progress through their development they become double-positive thymocytes


(CD4+CD8+)

• finally mature to single-positive (CD4+CD8- or CD4-CD8+) thymocytes that are then


released from the thymus to peripheral tissues

• About 98% of thymocytes die during the development processes in the


thymus by failing either positive selection or negative selection

• Only 2% survive and leave the thymus to become mature


immunocompetent T cells
RAG-1 & RAG-2 are required
For TCR rearrangement Receptor for
Stem cell GF

CD44 >adhesion
molecule
CD25> α chain of IL-2
Development of T cells
Positive selection
Immature T cells whose TCR
recognize and combine with
MHC molecules are selected

Immature T cells whose TCR


cannot recognize MHC
molecules are deleted

 MHC-I-------CD8+ expression
 MHC-II------CD4+ expression
Development of T cells
Negative selection
Immature T cells whose TCR
cannot combine with self
antigen peptide-MHC complex
develop and differentiate
continuously.

Immature T cells whose TCR


recognize and combine with
self antigen peptide-MHC
complex undergo apoptosis
Activation of genes
• Grouped into one of three categories depending on how early they are
detected after antigen recognition

• Immediate genes
Expressed within half an hour of antigen recognition. These include a
number of transcription factors, including c-Fos, c-Myc, c-Jun, NFAT, and
NF-kB

• Early genes
Expressed within 1 to 20 hours of antigen recognition, encodes IL-2, IL-2R,
IL-3, IL-6, IFN-ү, and numerous other proteins

• Late genes
Expressed more then 2 days after antigen recognition, encodes various
adhesion molecules
Multiple signaling pathways are initiated by
TCR engagement
• Many signal transduction pathways involve signal induced assembly of some
components of the pathway; these assemblies utilize adaptor proteins

• Signal reception often leads to the generation within the cell of a “second
messenger,” a molecule or ion that can diffuse to other sites in the cell and
evoke metabolic changes

• Protein kinases and protein phosphatases are activated or inhibited

• Many signal transduction pathways involve the signal induced assembly of


some components of the pathway

• Signals are amplified by enzyme cascades


The initiation of TCR signaling

Homodimer
Of Zeta

A protein tyrosine
kinase essential
for initiation of TCR
signaling
Phosphoinositol biphosphate
Inositol 1,4,5-triphosphate
Diacylglycerol

IL-2,IL-4
NF-ЌB

ADAPTOR PROTEINS - SLP76 (SH2-domain containing leukocyte


protein of 76 KDa and LAT (Linker of activated T cells).
ADAPTOR PROTEINS: 1) Serve as links for proteins, 2) Promote
assembly of membrane proteins
PLCγ= phospholipase C
The Ras/MAP Kinase
Pathway

Mitogen-activated protein kinase


pathway

A transcription factor
Necessary for the
expression of Fos

IL-2
Role of co-stimulatory signals
• The interaction of the multiple membrane associated
molecules is not sufficient

• Naïve T cells require more than one signal for activation and
subsequent proliferation into effector cells

• Signal 1: generated by interaction of antigenic-peptide with


TCR-CD3 complex

• Signal 2: generated by interaction of CD28 on T cells and


members of B7 family on APC
Clonal Anergy
• Anergy is a state of non-responsiveness, marked by the
inability of cells to proliferate

• If a T-cell encounters MHC:peptide but no co-stimulatory


signals are provided it will become anergic T-cell

• When anergic T-cell is now provided with an APC that can


deliver the co-stimulatory signal it is not able to respond

• Although clonal anergy has been known for years, its


significance is still not clear in vivo.
Lack of co-stimulatory signal results in
clonal anergy
Role of superantigens
• Proteins that bind simultaneously to TCR Vβ chain and α chain of MHC class II
and induce T cell activation and proliferation
• May be divided into
• Exogenous Superantigens are soluble proteins secreted by bacteria (exotoxins
secreted by Gram positive bacteria, such as staphylococcal enterotoxin)
• Endogenous Superantigens are cell-membrane proteins encoded by certain
viruses that infect mammalian cells

• activation by superantigens is polyclonal and can affect a significant


percentage of the total TH population

• massive activation results in overproduction of T helper cell cytokines,


leading to systemic toxicity

• food poisoning induced by staphylococcal enterotoxins and toxic shock


induced by toxic shock syndrome toxin
Activation of T cells generate effector and
memory T cells

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