T cells (improve) Flashcards
αβγδεμκλ
Cytotoxic T cell
MHC class I CD8
Functions:
- cytokine e.g IFNγ
- inhibition of viral replication
- macrophage activation
- killing of virus infected cells (cytotoxins)
- killing of tumour cells
Helper T cell
MHC class II CD4
Functions:
- help naive B cells + CD8 T cells
- activate macrophages
- cytokine secretion.
TCR structure
Differences/ similarities to BCR?
Closely related to single antibody Fab fragment. 2 polypeptide chains, each containing a constant and a variable region.
Individual domains are structurally related to the immunoglobulin fold domain. Molecules containing Ig like domains are members of the immunoglobin superfamiliy.
But (unlike BCR):
- monovalent
- membrane bound, no secreted counterpart
- does not undergo somatic hypermutation
- used solely for antigen recognition, not linked to effector function.
T-cell receptor rearrangement
Germ-line configuration: CD4-, CD8-
β chain rearrangement:
1) Dβ —-> Jβ
2) Vβ —–> DJβ
- β chain expressed on surface with surrogate (pre T) α chain. β chain reaching surface & successfully pairing with pTα signals it is functional- Stops β chain rearrangement. Allelic exclusion of 2nd β chain.
Cell expressing β & pTα is still CD4-/CD8-
Cell proliferates
CD4 and CD8 expressed -> cell is CD4+/CD8+
α chain rearrangement
- rearranges continuously until can successfully pair with β chain
- Vα —-> Jα (No D)
αβ TCR expressed at cell surface. +ve and -ve selection begins.
TCR complementarity determining regions
Variation concentrated in CDRs: 1, 2 and 3
CDR3 is most variable region, and is focused on VDJ junctions.
CDR3 makes the major contact with peptide present in the MHC groove
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T cell selection
1) successful β chain rearrangement
2) positive selection
3) negative selection
‘Eliminate the harmful, reject the useless’
Only ~1-2% of double +ve (CD4+/CD8+) thymocytes survive selection
Positive selection
Unique to T cells
Mediated by cortical epithelial cells. densely packed with immature rapidly dividing thymocytes, which continue rearranging their α chains- multiple opportunities for +ve selection.
- newly rearranged TCRs are tested against self peptide/MHC complexes
- TCRs with ‘moderate’ affinity for self MHC/peptide receive positive signal to continue maturation
- lack of interaction -> death by neglect. Positive selection is the major cause of thymocyte death.
Surviving cells will be CD4+ single positive if selected against MHC class II/peptide, CD8+ if selected against MHC class I/ peptide.
Negative selection
Helps prevent autoimmunity. Mediated mainly by bone marrow derived cells (dendritic cells & macrophages) in the thymus medulla.
Potentially autoreactive thymocytes expressing TCRs with ‘high’ affinity for MHC/self peptide are eliminated by apoptosis.
Cannot eliminate T cells with receptors recognising MHC/peptide combinations that are not expressed in the thymus- these are dealth with in the periphary
Structure of the thymus
Roles of each region?
Path taken by bone marrow precursors
Bone marrow precursors enter outer sub-capsular region, progress through cortex to medulla.
Cortex:
- cortical epithelial cells appear to be only cells capable of mediating +ve selection
- densely packed with immature rapidly dividing thymocytes, which continue rearranging their α chains- multiple opportunities for +ve selection.
Medulla (centre of lobe)
- medullary epithelial cells
- bone marrow derived cells: dendritic cells & macrophages. Appear to be most efficient at triggering -ve selection.
T cell activation
The 2 signal hypothesis.
Co-stimulation
Cells that survive selection enter the circulation as mature naive T cells. Must be activated by a professional APC to become functional.
Signal 1: delivered by TCR engagement
Signal 2: delivered by co-stimulatory molecules.
CD28 on T cell interacts with B7.1 (CD80) and B7.2 (CD86) on the APC
CD40L on T cell interacts with CD40
Professional antigen presenting cells
Defining feature- express co-stimulatory molecules:
CD40- interacts with CD40L on T cell
B7.1 (CD80) and B7.2 (CD86) - interact with CD28 on T cell
T helper cell subsets
Naive CD4 (TH0) can differentiate into TH1 or TH2 depending on
- nature of antigenic challenge
- cytokines (produced by DCs, macrophages & NK cells) present during proliferation
Differentiation occurs early in the immune response, and once established TH1/2 bias is self-reinforcing.
TH1 responses promoted/ inhibited by
Stimulated by - abundant antigen and high affinity TCR interactions - IL-12 (produced by macrophages) Inhibited by - IL-4 (produced by mast cells)
TH2 responses promoted/ inhibited by
Stimulated by - low peptide abundance or with weak affinity for antigen - IL-4 (produced by mast cells) Inhibited by - IFNγ (produced by NK cells)
TH1 responses: effects
Cell mediated immunity- imp vs intracellular pathogens e.g mycobacteria
Activate mainly macrophages, NK cells, CTLs.
Produce cytokines that
- support inflammation & cell mediated responses. e.g IFnγ
- boost production of IgG2a antibody in mice (NB FcγRIIa is found on macrophages & neutrophils, stimulated phagocytosis)
TH2 responses: effects
Essentially humoral. Activate mainly B cells & immune responses that depend on antibodies.
Production of cytokines that (in mice)
- promote B cell growth (IL-4, IL-6)
- promote IgG1 production (IL-4)
- promote IgA production (IL-5)
- promote IgE production (IL-4)
- stimulate effector cells which use these antibody isotypes: eosinophils (via IL-5) and mast cells (IL-4)
- inhibit macrophages (IL-10, anti-inflammatory)
