Nurse Shark T Cell Receptors Employ Somatic Hypermutation Preferentially to Alter Alpha/Delta Variable Segments Associated with Alpha Constant Region.

In addition to canonical T and B cell receptors, cartilaginous fish assemble non-canonical T cell receptors (TCR) that employ various B cell components. For example, shark T cells associate alpha (TCR-alpha) or delta (TCR-delta) constant (C) regions with immunoglobulin (Ig) heavy chain (H) variable (V) segments or TCR-associated Ig-like V (TAILV) segments to form chimeric IgV-T cell receptors, and combine TCRdeltaC with both Ig-like and TCR-like V segments to form the doubly-rearranging NAR-TCR. AID-catalyzed somatic hypermutation (SHM), typically used for B cell affinity maturation, also is used by TCR-alpha during selection in the shark thymus presumably to salvage failing receptors. Here, we found that the use of SHM by nurse shark TCR varies depending on the particular V segment or C region used. First, SHM significantly alters alpha/delta V (TCRalphadeltaV) segments using TCR alphaC but not deltaC. Second, mutation to IgHV segments associated with TCR deltaC was reduced compared to mutation to TCR alphadeltaV associated with TCR alphaC. Mutation was present but limited in V segments of all other TCR chains, including NAR-TCR. Unexpectedly, we found preferential rearrangement of the non-canonical IgHV-TCRdeltaC over canonical TCR alphadeltaV-TCRdeltaC receptors. The differential use of SHM may reveal how AID targets V regions. This article is protected by copyright. All rights reserved.