MHC antigens and T lymphocytes Flashcards
MHC
Major Histocompatibility Complex (termed Human Leukocyte Antignes, HLA, in man) 2 different classes in man, class I and class II. All the genes encoding these are highly polymorphic meaning that there is a large degree of variation within the population Matchjng HLAs variations between individuals is tbe basis of tissue typing for organ/tissue transplants between individuals (allograft)
Class I HLAs
Designated A, B and C
We inherit one from each parent
Thus we usually have 2 distinct A, B and C antigens on the surface of each cell (except RBC)
Class II HLAs
Designated DP, DQ and DR
Inherit one from each parent
Thus we usually have two distinct DP,DQ and DR antigens.
Expressed only on APCs (macrophages and dendritic cells)
T lymphocyte function
Arise in bone marrow but mature in thymus
Do not produce antibodies but bave surface receptors structurally related to Ig.
T cells see antigens in a different form from B cells, B cells refognise native antigen, T cells recognise processed antigen (MHC bound)
Two major T cell subtypes, defined on the basis of function, accessory molecule expression and type of MHC protein presenting antigen to them: CD8 and CD4
CD8 Cytotoxic T (TC) cells
See viruses growing inside infected cell
Window of processed viral peptide is presented at the cell surface by MHC class I proteins
T cell receptors (TCRs) on CD8 TC cells that recognise tne MHC class I Complexed peptide bind and then kill the infected cell.
Responsible for cytokine production and cytotoxic lysis of infected/tumour cells
Cytotoxic efector molecules include perforin and granzymes.
CD4 Helper T (TH) Cells
Circulating TH cells circulate and check for antigen. The mechanism for checking is Via TCR interface with MHC class II proteins on APCs and checking which peptide class II is presenting. If naive TH cell is stimuated by contect with the antigen, it proliferates, differentiates and produces lymphokines and chemokines. TH cell division (via autocrine production of IL-2) means that there are now lots of activated TH cells around to help out.
MHC Structure
Boat shaped groove on top of the MHC molecule binds peptide from intracellular pathogen (bacteria/virus) and presents the peptide within the groove to TCRs on T lymphocytes.
Peptide binding is very jigh affijity and essentially irreversible.
Because MHCs are highly polymorphic the abikity to present peptides (and thus respond to infection) varies between individuals.
Genetic diversity within anspecies is the key to responding to a wide range of infections.
Loading of pathogen derived peptides onto MHC class I
Intracellular pathogens are degraded by proteosomes (chopped up into small peptides) Peptides are then transferred jnto ER by TAP1/2 (transporters associated with antigen processing 1/2) Peptides displace chaperone proteins on MHC class I Complexed with B2 microglobulin. Onky now can peptide bound MHC class I-B2-microglobulin complex move from ER to cell surface where it can present antigen to TCR on CD8
Loading of pathogen derived peptides onto MHC class II
Extracellular pathogen is entrrnalised by endocytosis into endosomes. Intracellular proteases partially degrade pathogens into peptide fragments. Invarient chain (Ii) prevents TAP-derived peptides binding to MHC II in the ER. Once in vesicles Ii is cleaved to leave a clip fragment that blocks peptide binding to MHC class II Interaction of MHC class II with HLA-DM facilitates the release of clip and allows peptide to bind, highly regulated. Peptide bound MHC class II can now traffic to the cell surface for presentation to TCR on CD4 helper cells.
TH1
Type of CD4 TH cell.
Cellular immunity
Secretes interferon gamma and lymphotoxin to help CD8 TC and macrophages and NK cells to work better when fighting intracellular pathogens.
Interferon gamma also forms part of a positive feedback loop to make more TH1 cells and recruits other leukocytes to site, producing inflammation
TH2
Humoral immunity
Secretes several key lymphokines that help antibody-mediated fight against extracellular pathogens.
IL-4
IL-13
IL-5
These can inhibit each other during development, important to maintain balance.
Leprosy is due to ineffective TH2 response being produced when TH1 is needed.
HIV targets CD4 cells.
IL-4
Stimulates Ig class switching between B cells
Promotes IgE synthesis
Forms part of a positive feedback loop to make more TH2 cells.
IL-13
Promotes IgE synthesis
Recruits and activates basophils
IL-5
Attracts and activates eosinophils
TH17
Secretes IL-17, IL-6 and transforming growth factor B (TGFb) to help fight extracellular pathogens.
TGFb and IL-6 also form part of a positive feedback loop to make more TH17 cells