Cell Mediated Immune Response

T Cell maturation,Activation & Differentiation

Thymic selection of T-cell Repertoire

Positive selection- Ensures MHC Restriction,Takes place in cortical region of thymus, Involves interaction of immature thymocytes with cortical epithelial cells.TCR on thymocytes tends to cluster with MHC molecules on cortical epithelial cell. Negative selection- Dendritic cells & Macrophage bearing Class I & Class II MHC molecules interact with thymocytes bearing high affinity receptors for self Ag + self MHC molecules or self MHC molecules alone. These thymocytes undergoes negative selection by apoptosis.

TH- Cell Activation

Activation is initiated by interaction of TCR-CD3 complex with a processed antigenic peptide bound to a class II MHC molecules on the surface of APC. This interaction initiates a cascade of biochemical events that induces the resting TH cell to enter the cell cycle, proliferating & differentiating into memory cells & effector cells. Immediate genes-Express with in half an hour of Ag recognition encodes a number of transcription factors like- c-Fos, c-Myc,cJun,NFAT,NF-kB. Early genes-Expressed with in 1-2 hr,Encode IL-2,IL-2R,IL-3,IL6,IFN etc. Late genes-Expressed more than 2 days after Ag recognition, Encode various adhesion molecules.

TH- Cell Activation contd

Co-Stimulatory signals are required for full T-Cell activation. Clonal anergy ensues if a co-stimulatory signal is absent. Superantigens induce T-cell activation by binding the TCR & MHC II simultaneously.

T-Cell Differentiation
Naive T cells- Resting cells in the G0 stage of cell cycle. Characterized by condensed chromatin,very little cytoplasm and little transcriptional activity. Effector T cells-Two subpopulation TH1 & TH2 subset. Cytokine profiles are different.TH1 responsible for CMI mainly DTH & TC Cell response. TH2 responsible for AMI through B Cell activation. Memory T cells- Ag generated,generally long lived, quiscent cells that respond with hightened reactivity to a sudsequent challenge with same Ag, generating a secondary response.Express high levels of numerous adhesion molecules.

Comparison of Naive,Effector,Memory T-Cells

Property Co-stimulatory signal(CD28-B7) CD45 isoform Cell adhesion molecules(CD2 ,LFA-1) Trafficking patterns Naive T Cells Required for activation CD45RA Low Effector T Cells Not required CD45RO High Memory T Cells Not required Both CD45RA&RO High

HEV in Sec.Lymphoid tissue

Tertiary lymphoid Both tissues; inflammatory sites

Effector molecules produced by effector T Cells

Cell Type CTL Soluble effectors Cytotoxins(Perforins &Granzymes), IFN-,TNF- IL-2,IL-3,TNF-,IFN-,GM-CSF ( High) IL-3,IL-4,IL-5,IL-6,IL-10,IL-13, GM-CSF(Low) Membrane bound effectors Fas ligand(FASL)

TH1

TNF-

TH2

CD40 ligand

Cytotoxic T Cells
CD8+ T-Cells, MHC Class I restricted,Can recognize & eleminates almost any altered body cells. Mediates CMI in two phases1) First phase activates & differentiates naive TC cells into functional effector T cell. 2) Second phase effector CTLs recognize AgMHC classI complexes on specific target cells, which leads them to destroy the target cells.

Generation of CTLs from CTL-P

Naive TC cells are functionally immature & are known as CTL Precursors (CTL-P). Generation of CTL require at least three sequential signals1)An Ag specific signal 1 transmitted by TCR complex upon recognition of peptide-MHC class I molecule. 2) A co-stimulatory signal transmitted by CD28-B7 interaction of CTL-P & APC. 3) A signal induced by interaction of IL-2 with high affinity IL-2R resulting in proliferation & differentiation of Ag activated CTL-P into effector CTLs.