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Immuno Generation of Diversity and T-cell developement TB Notes.docx

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Health Sciences
Jonathan Bramson

THE GENERATION OF DIVERSITY LECTURE Germline  One gene per receptor and this was inherited (Likely not the feasible option)  Not ALL wrong because you do still inherit receptors Somatic Diversification  Recombination of limited number of gene sequences  Sequences are inherited VDJ Recombination (FOR BCR)  Have genes: V (variable segment), D (Diversity), J (joining), C (constant), L (leader sequence= targets calls for secretion?)  Light chain recombination (VJ) o -------L-V-------J------C----- (all gaps are introns= removed) o Following recombination you get -----L---VJC----------------- o At this point= remove all introns= -----LVJC-----------------  Heavy chain recombination o -----L—V---D—J----C-C—C—C o Step1= D joins J (----L—V—DJ-------) o Step 2= V joins DJ (-----VDJ------) o Step 3= C spliced with VDJ (--LVDJCCCC) o There are MANY V and J regions= therefore depending on which ones recombine, you will get a different diversity VDJ Recombination (FOR TCR)  Similar to the BCR recombination  Alpha chain= undergoes VJ recombination  Beta chain= VDJ recombination Two problems 1. Want to make sure that the recombination occurs correctly 2. Want to make sure that V and J goes together  Answer: Recombination signal sequence (RSS) o ----heptamer---spacer seq----nonamer o Spacer is either= 23 base pairs (x2 turns of the helix) or 12 base pairs (x1 turn of the helix) o Rule= Spacer is right next to the gene segment  -----V-(23RSS)----------------(12RSS)-J-----  OR -----V-(23RSS)--------- (12RSS)D(23RSS)--------(12RSS)-J----- Recombining  In the forward orientation= looped out DNA is excised= V and J recombine at the heptomer sequences (Thus, x2 RSS and other fragments are spliced out)  In the reverse orientation = nothing is excised out= LVG all brought close together What mediates this?  V(D)J recombinase= contains RAG-1 and RAG-2= only expressed before maturation (i.e. before recombination)  Deficient in these enzymes= no maturation of T and B cells Junctional Diversity  Random addition of bases = mediated by Terminal deoxynucleotidyl transferase (TdT)  Excision of bases that do not match up = mediated by exonuclease  Because random= risky because frame shifts to occur= NON-PRODUCTIVE REARRANGEMENT Somatic Hypermutations  Point mutations in the variable regions of the BCR chains (light and heavy)  Only occurs in mature/activated B-cells that have seen their antigen  Stressful time for B-cell= to generate/increase affinity for antigen (AFFINITY MATURATION)  Completely random  If successful: turn into mature antibody producing B-cell  These cells are favored for survival Recap: Generating diversity:  Combinatorial diversity o V, D, J segments o Different chains= i.e. can different heavy and light chains binding (i.e. BCR= light and heavy, TCR= alpha:beta, gamma:delta)  Junctional diversity (BCR and TCR)  Somatic Hypermutation (B-cell) T Cell and B-Cell Development  T cells mature in the thymus o Positive selection= MHC Restriction o Negative selection= Central Tolerance (i.e. want to be able to tolerate yourself)  B cells in the bone marrow o Negative selection= in the bone marrow= i.e. do not want antibodies binding to self o NO POSITIVE SELECTION= NO NOTE: NUDE MOUSE= NO THYMUS BUT FUNCTIONAL CELLS NOTE: SCID MOUSE= THYMUS, BUT NO FUNCTIONAL CELLS T-CELL DEVELOPEMENT *** KNOW STRUCTURE OF THYMUS  Cortex= outer region= immature thymocytes o Cortical epithelial cells= important for selection= a
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