Antibodies and T Cell Receptor Genetics Generation of Antigen Receptor Diversity

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1 Antibodies and T Cell Receptor Genetics 2008 Peter Burrows peterb@uab.edu Generation of Antigen Receptor Diversity Survival requires B and T cell receptor diversity to respond to the diversity of pathogens The immune system must Be Prepared to respond to antigens it has never encountered One to 100 million different antigen receptors (Ig on B cells, TCR on T cells) can be produced

2 Generation of Diversity Cellular Solutions Diversity operates at the level of the lymphocyte Each lymphocyte has a unique receptor for antigen Produce one million different lymphocytes per day Antigen selects cells by binding to a complementary receptor and stimulating cell division and differentiation (antibodysecreting plasma cells or effector T cells) Antigen Selects Lymphocytes Isotype Switch

3 VL VH IgM B Cell VH VL Antigen-Antibody Binding

4 Generation of Diversity Survival requires diversity to respond to the diversity of pathogens One to 100 million different antibodies can be produced Nine isotypes Similar numbers of T cell receptors for antigen Problem - Not enough DNA to support observed diversity 10 x 10 6 genes X 10 3 base pairs DNA/gene = 10 x 10 9 bp > 3 X 10 9 bp DNA available Anatomy of a gene

5 Anatomy of Immunoglobulin Genes in B Lymphocytes Intron Exon Exon DNA mrna Protein Generation of Diversity Genetic Solutions Functional genes for antigen receptors do not exist until they are generated during the development of lymphocytes Variable region exons are formed by splicing together segments of genes inherited through the germline The process is called Ig or TCR gene rearrangement, and generates tremendous diversity without monopolizing the genome

6 Variable region genes are constructed from gene segments Germline DNA B Cell DNA mrna Protein Germline Ig Genes

7 V-region Gene Segments are Joined by Somatic Recombination Somatic recombination at the Ig heavy chain locus * * Germline DNA * D J H rearrangement V DJ H rearrangement Primary RNA transcript Splicing and polya mrna Nascent polypeptide Mature heavy chain protein

8 Benefits of Antigen Receptor Gene Rearrangement 40 Vκ 30 Vλ 65 VH x 5 Jκ x 3 Jλ 27 DH x 6 JH 200 κ V regions 90 λ V regions 10,530 H V regions How many antibodies can be made? (10,530 HC) x (200 κ LC) = 2.1 x 10 6 IgM κ antibodies (10,530 HC) x (90 λ LC) = 0.9 x 10 6 IgM λ antibodies 3 million total Not bad from 176 gene segments! One B cell or plasma cell only makes one antibody Isotype Switching Also Occurs by Somatic Recombination

9 Switch Recombination Advantage No requirement for separate VDJH recombination for each isotype Only cells that switch will be those responding to antigen Features Irreversible Individual plasma cell produces one isotype one specificity Primary and Secondary Antibody Responses Primary Secondary Higher titer Higher affinity 1998 Gold Standard Multimedia Inc.

10 The T Cell Receptor for Antigen TCR Structure of the T-cell Receptor

11 The T Cell Receptor Heterodimer that only exists as a transmembrane antigen receptor It is not secreted since T cells function by direct cell contact The variable regions of the TCR are generated by somatic gene recombination as the T cells develop in the Thymus The process is identical to Ig gene rearrangement, but different genes are used T-cell Receptor α- and β-chain V Regions are Generated by Gene Segment Rearrangement

12 Comparison of the TCR and the BCR (Immunoglobulin) V regions encoded by rearranging genes B cells recognize intact protein antigens Heavy Chain Lysozyme Antigenic Determinant Epitope Light Chain

13 T cells recognize processed (degraded) protein antigens Dangers in Diversity Mechanism is essentially a random draw By chance, some Ig and TCR will react with self antigens Autoreactive B and T cells must be eliminated or silenced to prevent autoimmune diseases Chromosomal translocations arising during VDJ recombination or isotype switching may lead to lymphoid malignancies