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
TREG
Secrete IL-10 and TGFb
Have immunosuppressive function
Suppresses activation of the immune system to prevent pathological self reactivity (autoimmune disease)
TH cells and stimulation of Antigen-specific antibody formation
Based on interactions between antigen, antigen-specific B cells, and antigen-specific Th cells. If an antigen in the blood encounters a B cell with a surface Ig that recognises that antigen, some of the antigen is bound by the surface Igs and some of it is endocytosed into the B cell. Endocytosed antigen is partially degraded and loaded onto the MHC class II as described earlier. The surface bound antigen cross links the surface Igs, these act like receptors and transmit a signal causing the B cell to synthesis B7 and MHC class II proteins. B7 activates TH cell when bound to CD28 and MHC class II is bound to TCR. Th cell then expresses CD40 ligand and cytokines are secreted. Cytokines bind to cytokine receptor, CD40 binds CD40 ligand and B cell is activated.
Viral infection
Virus enters cell, infects cell, cel, lyses then vrius infects neighbouring cells.
Innate immune system kicks in due do viral componants activation pattern recognition receptors. This stimulates dying cells to release cytokines to alert immune system. Interferon alpha and beta have immediate antiviral effects, as they activate NK cells, increase MHC class I + TAP1/2 expression in all cells.
PAMP receptors activate tissue resident Marcophages to release cytokines and chemokines. Released cytokine induce acute phase response and recruitment of phagocytes.
Acute phase response
Produces a range of mediators that bind patjogen derived molecules but not those of the host.
Produced by liver cells in response to cytokines, released by bacterial-PAMP-activated macrophages at site of infection.
C-reactive protein (CRP) - opsonisation, activates complement.
Mannose binding lectin (MBL) - opsonisation, activates complement.
Fibrinogen - coagulation
SP-A/D - bacterial surfactants, opsonisation
Tissue resident dendritic cells
Hoover up rubbish, process it and migrate to wthe nearest lymphnode.
Here DCs present processed antigen to entering TH and TC cells, those few ceels that recognise the antigen proliferate, become activated and generate more cytokines. Activated TH cells also stimulate B cell proliferation and plasma cell antibody production.
Activated T cells now leave via efferent lymph, thoracic lymph into systemic blood circulation.
Th cells are covered in chemokine/cytokine receptors and adhesion molecules.
Adhesion molecules guide specific recruitment to site of infection. (T cell pathogen induced recruitment).
The hygiene response
Modern obsession with cleanliness is counter productive in childhood, resulting in the development of an immune system that is too sensitive to infection on exposure to common environmental antigens in later life.
Hypothesis expanded to include increased incidence of IBS, MS, and type 1 diabetes.
Reduced Treg mediated supression of TH2 cells, reduced TGFb and IL-10.
