T-cells, effector functions and the MHC Flashcards
How do T cells recognise antigens?
-Peptides are displayed by cells in the
context of highly polymorphic MHC molecules
MHC I vs MHC II
MHCI
-Associates with B2 microglobulin
-Endogenously expressed on all nucleated cells
MHCII
-Alpha beta Hetrodimer
-Expressed on specialized antigen presenting cells: Monocytes, Macrophages, Dendritic cells, B lymphocytes
What does T cell see on surface of APC
-Peptide made from 8-15 amino acids
What peptides do MHC I and MHC II present
MHC I
-Present peptides derived from proteins currently being synthesised in that cell (endogenous)
MHC II
-Present peptides derived from antigens that they’ve pulled in from outside (exogenous)
How does MHC I present peptides
-Virus infects cell
-Virus hijacks host protein production machinery
-Host cell breaks down sample of all of the proteins being produced in the cell using proteosome
-Peptides are transported to ER, where they are converted to newly synthesised MHC class I molecules
-These molecules are presented on cell surface, displaying the peptide to the immune system (shop window)
How does MHC II present peptides
-MHC II molecules mainly display peptides derived from exogenous antigens
-These are taken up by receptor mediated uptake or endocytosis
-Endocytic vesicles contain proteolytic enzymes that will degrade proteins
-Simultaneously MHC II molecules are synthesised in ER
-These molecules migrate to late endosomes where they fuse with vesicles
-In vesicles, peptides are loaded into MHC II molecules, which are transported to cell surface and presented to immune system
Where are the genes encoding MHC I and II found in humans?
-Short arm of chromosome 6
-Most polymorphic region of human genome
-This region is called the ‘Human Leukocyte antigen’
-Polygenic region - several MHC class I and II genes encoding for separate molecules
How many genes encode MHC class I
-3 distinct genes leading to 3 related but different HLA proteins
-HLAa, HLAb, HLAc
-3 pairs of genes encoding for 3 different HLA class II molecules
-HLAdr, HLAdp, HLAdq
-HLA region is also polymorphic - many alleles (variants of each gene) exist
-Codominantly expressed - one allele from mum and dad, express both
How does HLA protect against pathogens?
-Polymorphic and polygenic of HLA make it difficult for pathogen to evade immune response
-Evolve antigen that doesn’t bind to any HLA molecules
Features of T cell receptor
-Membrane bound hetrodimer
-2 chains joined by disulphide bonds
-Two subtypes: alpha beta and gamma delta T cells
-Consist of variable and constant domains
-T cell receptor genes undergo rearrangements from germline before translation
T cell receptor selection
Fruit machine analogy
-T cell randomly selects elements for each domain of the alpha and beta chain
-Chains then combine to give the particular T cell receptor
-Unlike B cells, T cells cannot undergo affinity maturation to change configuration
What determines whether T cell will respond to peptide presented by MHC?
-Interaction between T cell receptor with combination of peptide and MHC
2 main classes of alpha beta T cells
CD8+ T cells:
-React with peptides presented by MHC I molecules
-They co-express a receptor called CD8+ which interacts with conserved part of MHC I molecules
-‘Cytotoxic T cells’
CD4+ T cells:
-React with peptides presented by MHC II molecules
-They co-express a receptor called CD4+ which interacts with conserved part of MHCII molecule’s
-‘Helper T cells’
2 steps to T cell activation
Signal 1:
-T cell receptor interacts with peptide MHC complex (provides specificity)
Signal 2:
-CD86 on APC binds to CD28 on T cell which transmits second signal (costimulation)
-Costimulatory molecules upregulated on APC by ‘danger signals’
=>infection
=>inflammation
-When T cells receives these signals it divides and produces cytokines
How do CD8+ T cells kill virus infected or cancer cells?
-Seek out and destroy cells
-Direct approach to killing cells
E.g.
-Cell to cell interactions
-Secretion of cytolytic cytokines (perforin and granzymes)
How do CD4+ T cells kill pathogens
-Activated CD4 cells can differentiate
into different kinds of effector T cells
with distinct functions
What can CD4+ T cells differentiate into?
-T helper cells which secrete different cytokines
-Regulatory T cells which modulate activity of other immune cells
Th1 cells
-Fight against viruses and pathogens
-Secretion of IL-2 helps cytotoxic CD8+ cells, allowing them to differentiate and express perforin and granzymes
-Secretion of IFN-y promotes macrophage differentiation, helps them to hone to sites of infection
Th2 cells
-Fight against extracellular parasites
-Produces IL-4 and IL-13 which help B cells to divide, class switch, affinity maturation
-Also allow differentiation of B cells into plasma cells which secrete anitbodies into serum
-Activate eosinophils by secretion of IL-4 and IL-5
Th17 cells
-Fight against extracellular bacteria
-Secrete IL-17, IL-21, IL-22 which help epithelial and fibroblast cells to secrete antimicrobial peptides, as well as wound healing
-Mature neutrophils and attract them to site of infection by chemotaxis
What do Treg cells do
-Downregulate immune responses by cell to cell contact or secretion of cytokines (TGF-B, IL-10)
-Suppress stimulatory activity of APC
-Suppress proliferation/cytokine production of responder cells
-Suppress antibody production from B cells
-Suppress functions of NK/NKT cells
