Revision of the antigen receptor of T-lymphocytes

Abstract

This review considers a crucially new mechanism of T-cell antigen-recognizing repertoire formation. It includes the revision of T-cell antigen receptor (TCR), which implies the secondary rearrangement of TCR genes in peripheral T-lymphocytes and surface expression of a new antigen receptor with altered specificity. Factors and mechanisms involved in the induction of this process have been analyzed. Certain attention is paid to a possible role of TCR revision in the formation of peripheral tolerance in the processes of "avidity maturation" of T-lymphocytes during immune response and also negative consequences related to appearance of potentially autoreactive clones in the periphery.

Somatic hypermutation of T cell receptor α chain contributes to selection in nurse shark thymus

“…In the absence of a complete germline sequence for this locus, we limited our database for TcRα to thymocyte clones with the same unique CDR3 signature. The CDR3 region results from the somatic recombination and assembly of variable (V) and joining (J) gene segments during lymphocyte development in the thymus ( Kuklina, 2006 ; Lantelme et al, 2008 ). The recombination process cleaves DNA and initiates repair mechanisms that result in the random insertion of non-template (N) nucleotides within the join, forming a unique binding sequence that contributes to the diversity and specificity of a TcR ( Gellert, 2002 ; Kuklina, 2006 ).…”

“…The CDR3 region results from the somatic recombination and assembly of variable (V) and joining (J) gene segments during lymphocyte development in the thymus ( Kuklina, 2006 ; Lantelme et al, 2008 ). The recombination process cleaves DNA and initiates repair mechanisms that result in the random insertion of non-template (N) nucleotides within the join, forming a unique binding sequence that contributes to the diversity and specificity of a TcR ( Gellert, 2002 ; Kuklina, 2006 ). Once recombination ceases and the thymocyte proliferates, this distinctive CDR3 sequence is perpetuated in all daughter cells ( Murphy and Weaver, 2017 ).…”

Role of CD40-Dependent Signal in Induction of Recombinase RAG-1 Expression in Peripheral T Cells of Patients with Autoimmune Diabetes Mellitus

“…Of the two recombinases involved in the process, RAG-1 possessing nuclease activity plays a key role in rearrangement [1,5], while the second recombinase RAG-2 is presumably required for stabilization of RAG-1 binding with DNA [3] and is not obligatory condition for rearrangement [1,5]; therefore, detection of RAG-1 is enough for making conclusion about activation of gene rearrangement.…”

“…Differentiation of immunocompetent cells outside the central immune organs, e.g. extrathymic differentiation of T cells, can be a solution [1]. The assumption stems from the absence of conditions for effective clonal selection providing elimination of autospecifi c T cell clones in peripheral organs, in contrast to the thymus; therefore, the formation of T lymphocytes outside the thymus should inevitably lead to the appearance of autoreactive cells and creates prerequisites for the development of autoimmune processes.…”

Of the multiple mechanisms leading to type 1 diabetes, T cell receptor revision may play a prominent role (is type 1 diabetes more than a single disease?)

“…In the periphery, at least, CD40 interacts directly with the RAG(s) complex in the nucleus . Following induction of RAGs, altered expression of TCR‐α and TCR‐β molecules on long‐standing peripheral T cells occurs . A central paradigm of immunology holds that once T cells exit the thymus TCR molecules do not undergo alteration.…”