The TCR[beta] chain consists of variable (V), joining (J), diversity (D) and constant (C) regions encoded by gene segments spanning 685 kilobases of human chromosome seven. Diversity and antigen specificity of T-cell antigen recognition is primarily attributed to the hypervariable, or third complementarity-determining region (CDR3), or the TCR[beta] chain, and is achieved by non-templated nucleotide additions or deletions during TCR gene rearrangements. Antigen driven T cell responses are observable as perturbations in the Gaussian-like distributions of CDR3 gene fragment lenghts of TCR families, because responding antigen-specific cells are retained in the memory lymphocyte pool, permanently altering the distributions of cells within the T cell repertoire. Therefore, analysis of CDR3 lenghts provides an assessment of the frequency and diversity of the T cell response to antigenic exposure.

Both central and effector memory subsets express disturbed repertories. Some BV families are overexpressed, especially in the effector CD62L- subset.

T cell Receptor Signalling:

Following the engagement of the TCR by the peptide/MHC, lymphocyte-specific protein kinase (LCK) is activated and phosphorylates CD3 immunreceptor tyrosine bassed activaiton motifs (ITAMs). Phosphorylated ITAMs recruit and activate ZAP-70 which in turn phosphorylates two key adaptor molecules, linker of activated T cells (LAT) and SLP76. SLP76 is recruited to membrane bound phospho LAT by Gads and facilitates the activaiton of IL-2 inducible tyrosine kinase (ITK). ITK dependent phosphorylation of phospholipase C-y1 (PLC-y1) at the membrane leads to dyrolysis of phosphatidylinositol diphosphate to inositol trisphosphate and diacylglycerol as we as release of Ca2+ from endoplasmic retriculum stores. This results in massive Ca2+ influx, activaiton of Erk, and reorganiztion of the actin cytoskeleton, leading to cellular activaiton. The aim of this process is to develop a fully activated T cell in a context dependent manner that will lead to diverse outcomes, such as promotion of thymic slection, T cell differentiation, migration and rlease of effector cytokines during acute resposnes. Genetic defects causing severe immunodeficiencies have been reported in many of the protein involved in the initiation of this casdcade, including the CD3 usbunits.(Lve “inherited SLP76 deficiency in humans cause severe combined immunodeficiency, neutrophil and platelet defects. JEM)