We propose to investigate, starting from experimental data recently obtained by us, the contribution of somatic mutations to T helper cell diversity. Further, we will attempt to establish, using T cell receptor mutants, the relationship between gene structure and receptor reactivities. In particular, we will: (i) elucidate the nature of genomic changes responsible for the acquisition of new patterns of T cell receptor reactivities by cloning and sequencing the Alpha and Beta cDNA clones from functionally characterized sets of parent and mutant offspring T cell hybridomas. (ii) analyze the occurence of T cell receptor mutations in vivo post-immunization (iii) attempt to assign biological significance (as estimated functionally by antigen specificity) to mutations occurring in particular sites on either Alpha and Beta variable regions via gene transfer of mutant gene into the appropriate T cell recipients. (iv) investigate the events and conditions resulting in T cell receptor mutations. The relationship between T cell receptor mutations, self and non-self discrimination and autoimmunity is obvious. The possibility of T cell receptor mutants becoming viral receptors, in the context of existing knowledge, could be significant for the understanding of the pathology of lymphoid tumors.
|Sim, G K; MacNeil, I A; Augustin, A A (1986) T helper cell receptors: idiotypes and repertoire. Immunol Rev 90:49-72|