Lecture 4 - The adaptive immune system, T cell and MHC Flashcards
What is the principle of clonal selection?
1) Single progenitor cell gives rise to a large number of lymphocytes each with a different specificity and receptor arrangement
2) Specificity of immature lymphocytes is tested against self antigens
3) Potentially self reactive immature clones are removed
4) Mature niave lymphocytes tested against foreign antigen
5) Lymphocyte specific to antigen is activated
6) Proliferation and differentiation of activated specific lymphocytes forms a clone of effector cells
7) Effector cells find and remove antigen from body
What is the principle of clonal selection?
1) Single progenitor cell gives rise to a large number of lymphocytes each with a different specificity and receptor arrangement
2) Specificity of immature lymphocytes is tested against self antigens
3) Potentially self reactive immature clones are removed
4) Mature niave lymphocytes tested against foreign antigen
5) Lymphocyte specific to antigen is activated
6) Proliferation and differentiation of activated specific lymphocytes forms a clone of effector cells
7) Effector cells find and remove antigen from body
What are the two types of T cells?
T helper
T Killer
What coreceptor do T helper cells express?
T helper cells express CD4
What co receptor do T killer cells express?
T killer cells express CD8
What class of MHC molecule to T helper cells interact with?
T helper cells interact with MHCII, to help B cells make entibodies
What class of MHC molecule do T killer cells interact with?
T killer cells interact with MHCI to kill infected cells
What is the struture and function of the T cell receptor?
2 chains, alpha and B chain
- alpha = contains V and J regions
- beta = contains V, D and J
- stalk segment (transmembrane bound region), stick out above membrane to be able to interact with MHC molecules
- cytoplasmic tail inside T cell
- chains joined by disulphide bond
- carbohydrates attached to chains
- not secreted but attached to the membrane of the T cell
How is diversity produced in the T cell receptor?
Same genetic recombination as in B cell but with the alpha and beta genes instead
What is the process of recombination to increase diversity in the T cell receptor?
1) begin with genomic DNA containing multiple V, J (D) regions attached to RSS elements
2) RAG recombinases recognise 23 bp motif and 12 bp motif and brings them together in a RAG complex
3) RAG complex formation leads to cleavage of signal sequences leading to a closed hairpin structure (covelently closed hairpin ends) and removal of piece of intervening circular DNA
4) Neuclease arrives to ‘nick’ DNA at ends to open it, activating DNA leading to pairing of strands
5) TdT (transferase enzyme) adds in random nucleotides
6) Exonuclease and ligase repair DNA
What types of elements are attached to the V, J and D regions in T cell genome?
V - 23 bp RSS downstream from gene
J - 12 bp RSS upstream from gene
D - 12 bp RSS upstream, 23 bp downstream
Why does recombination only occur in lymphocytes?
the process id dependent on the RAG recombinases RAG1 and RAG2 which are only expressed in lymphocytes
Features of the RAG genes
- Both RAG1 and RAG2 required for recombination
- retroviral insertions
- no introns
- head to tail, rare in mammals
Why don’t B cells rearrange TCR, why don’t T cells rearrange antibody genes, as they have the right enzymes.
Because of chromatin accessibility = recombination requires open DNA for enzymes to work, therefore in B cells antibody genes are in open chromatid not TCR genes
What is the structure of MHCI molecule?
3 alpha components, beta microglobulin peptide binding cleft underneath beta sheet
What are the properties of the MHCI molecule?
- important role in killing virally infected cells
- made inside cell
- loaded with peptides cell has exported to surface
- expressed on all nucleated cells
How do peptides bind onto MHCI molecules?
- peptides hydrogen bond onto beta plate
- specific binding motifs of specific amino charged amino acids in specific places allow binding of charged residues to beta plate
- peptides must be right length, 8/9 amino acisd
How do T cell receptors interact with MHCI/peptide complex?
hyper variable loops on TCR interact with the peptide bound to the MHCI and to the MHCI itself
What is the structure of the MHCII molecule?
made up of two chains, alpha and beta
What is the difference between MHCII and MHCI molecules?
MHCII have open ends to fit longer peptides
How do peptides bind to MHCII molecules?
in peptide binding cleft, like MHCI, specific amino acids in peptides are required for binding and can vary in length
What are the origins of the MHCII?
1) dendritic cells phagocytose antigens/antigens bind to B cell surface receptor and are internalised
2) degraded to peptide fragments
3) fragments bind to MHCII and are transported to cell surface
4) helper T cells bind to MHC complex and activates B cell to produce antibodies
What are the two types of coreceptor, CD4 and CD8, for?
Not strong enough to activate alone, hold in place, increase affinity
What is the MHCI coreceptor?
CD8 (killer T cell) binds to MHCI
