Lecture 15 - Lecture 15- T Cell Development 5.9-5.11;...

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Lecture 15- T Cell Development 5.9-5.11; 8.7-8.14; 8.15-8.22 The TCR Many similarities to the BCR/Ab; looks like FAB portion (smaller than BCR) α/β chains; each with 2 Ig domains V and C regions CDR1, 2 and 3 in the V region Signalling mediated through a molecular complex: CD3 and 2 ζ chains (form a homodimer) CD3’s have ITAMs CDRs found in coding region involved with antigen binding region CDR3= generally found in center interacting with where the peptide binds; highly variable CDR1/2 are more on the periphery and mainly recognize MHC TCR: peptide: MHC binding: Large complex of molecules Co-receptor: CD4—MHCII CD8—MHCI Assembly of complex initiates signalling 2 functions: A) stabilizes interaction between TCR and peptide (makes the bond stronger) B) constitutively associated with LCR and brings this close to ITAM; LCR phosphorylates ITAM and the signal is set in motion See diagram Thymic Development of T Lymphocytes: Starts in the bone marrow Derived from common lymphoid progenitor; enters circulation and enters thymus to become a T-cell Thymus Thymectomy—thymic involution; largest in pre-adol. Nude mice/ DiGeorge Syndrome (very few T cells) Right above heart Creates environment necessary for T-cell development Made of microdomains: outer cortex and inner medulla At different stages of development the cell changes migratory habits and location in the microenvironment How T cells develop is based on where they are located (immature—cortex, developing—medulla) Thymic Development of T lymphocytes Begin as “double negative”- doesn’t express CD4 or CD8 Moves up into cortex and begins to recombine TCR starting with B chain Recombination: similar to B cell VDJ recombo; 12/23 rule holds Heptamer signal sequence: CACAGTG; nonamer sequence: ACAAAAACC The B chain resembles the heavy chain: has a V D and J Role of CD25? B chain rearrangement Many V genes, single D, small number of J’s and a constant domain; followed by another D and J and C etc; NOT the same as isotype switching Decision of what constant region to use is determined during primary rearrangement Look at VDJ recombination process; breaking the hairpin loop creates palindromic sequences (can loop back on itself; P-nucleotides); N nucleotides are randomly added by TdT
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Randomness generated through P and N nucleotides; palindromic sequences with N nucleotides in middle CDRs in the TCR CDR3- formed from the joining region: VDJ for B chain and VJ for αchain; interacts with peptide CDR1/2- germline encoded; in the V gene; there is still many V genes so lots of diversity A lot of diversity comes from multiple V, D and J regions Alpha chain has many J segments so diversity from that too Diversity from P and N nucleotides and junctional diversity There is a place holder for the alpha chain(pTα chain) in a pre T cell= germ line encoded. .completely separate protein;
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Lecture 15 - Lecture 15- T Cell Development 5.9-5.11;...

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