5-T Cells - Cell Mediated Immunity

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Ontogeny of T lymphocytes-

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Requires - Thymus to mature

prothymocytes from bone marrow --> thymus (thymocytes) --> differentiate into mature T cells

--> peripheral lymphoid organs

Memory T cells - in bloodstream respond

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CD4+ subsets:

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T helper lymphocytes

TH1: cell mediated immunity (IgG)

TH2: humoral immunity (IgE)

TH17: inflammation

Tfh: germinal center in lymph organs

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CD8+ subsets:

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Cytotoxic T lymphocytes "CTLs"

-lyse virus infected cells

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T cell antigen receptor (TCR)

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• recognize and respond to antigen
• not responsible for MHC restriction
• CD4+ and CD8+ restricts TCR
• Heterodimer of disulfide linked alpha and beta chains
• each chain with CONSTANT and VARIABLE region

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T cell antigen receptors - characteristics

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• Both chains - bind antigen and MHC
• cytoplasmic tails not long enough to act as signal transducers---> REQUIRES CD3
• embedded in membrane - never secretted

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T cell receptor vs. B cell receptor

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TCR - single antigen binding site

BCR - two sites

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TCR and CD3

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CD3 - every Tcell has them

Low CD3 = Low T cell count

Allows signal transduction that Tcells can't do (TREX ARMS)

phosphorylation site on cytoplasmic tails for signal transduction

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TCR and Co-Stimulatory Molecules-

CD28:

CD40:

B7:

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• Needed for T-cell response
• aids by triggering signal transduction
• CD28: binds B7
• CD40: ligand CD40L binds to CD40
• B7 and CD40 expressed on ALL professional antigen presenting cells

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CD4+ Characteristics / Functions:

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CD4+ : MHC class II

Most are T Helper cells

attacked by HIV

Transmembrane glycoprotein w/ a single polypeptide

Functions:

Cell adhesion molecules

signal transduction

restricts T cell responses to recognize only CLASS II MHC prot

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CD8+ Characteristics / Functions:

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CD8+ : MHC class I

Most cytotoxic T lymphocytes

homodimer or heterodimer

Functions:

Cell adhesion

signal transduction

Restricts T cell responses to recognize only class I MHC prot

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Signal Transduction: TCR binds to MHC bound antigen

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clustering of TCRS w multiple MHC peptide complexes

as few as 10 MHC peptide complexes can trigger T cell activation

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signal transduction: Early activation events

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phosphoinositide pathway, RAS, MAP kinase pathway activated

protein kinase C and other kinases phosphorylate transcription factors

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signal transduction: Gene transcription

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transcription factor AP-1 initiates IL-2 cytokine production

Interleukin-2 (IL-2) and IL-2 receptor produced for AUTOCRINE growth

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signal transduction: Mitosis

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expands antigen specific clones to amplify an immune response

mitosis detected 48-72 hours after stimulation through the TCR

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Development of TH1 cells:

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TH1: Cell mediated immunity

Inflammation by bacteria, viruses or other pathogens

--> Interleukin-12 (IL12) --> TH1

cell mediated response:

interferon-gamma (IFN-y) and activating macrophages and CTLs

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TH1 mediated immunity - CTL's

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"cross presentation"

CD4+ helper T cells produce cytokines that stimulate CTL differentiation

CD4+ helper T cells enhance ability of APCs to stimulate CTL differentiation

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Development of TH2 Cells:

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IgE production - antiparasite defense "worms"

Mast cells / antigen activated T cells -->

Interleukin-4 (IL-4) --> TH2

Absence of Inflammation: default to TH2 pathway

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Development of TH17 Cells:

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Anti microbial defense - inflammatory cytokines

IL-1, IL-6 and transforming growth factor-beta (TGF-B) --> TH17

IL-23: from dendritic cells to stabilize TH17

IL-17 and IL22---> promote inflammation

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Regulation of TH1 and TH2 responses:

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IFN-y: inhibits TH2

IL-4 and IL-3 inhibit TH1 (macrophage activation)

immunes responses dominated by TH1 or TH2

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macrophage activation:

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"cell mediated immunity"

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CTL activation:

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Function: destroy INTRACELLULAR microbes (viruses, some bacteria, some tumor cells, transplanted tissues)

part of "cell mediated immunity" stimulated by TH1 cells

Recognize endogenous peptide presented on class I MHC through antigen recognition through the TCR and binding of CD8

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CTL killing process (5 steps)

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1. target cell binding and recognition of class I MHC and antigen

2. CTL activation

3. Delivery of the lethal hit

4. disengagement from the target cell to attack other target cell

5. Death of target cell

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CTL killing mechanisms:

primary and secondary

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principle mechanism:

perforin facilitates delivery of granzyme B to target cell cytoplasm which activates caspase pathway --> target cell death through MITO pathway of apoptosis

secondary mechanism:

binding of CTL expressed Fas ligand to target cell Fas protein --> activates caspases --> apoptosis