Nurse shark T‐cell receptors employ somatic hypermutation preferentially to alter alpha/delta variable segments associated with alpha constant region

Abstract

In addition to canonical TCR and BCR, cartilaginous fish assemble noncanonical TCR that employ various B‐cell components. For example, shark T cells associate alpha (TCR‐α) or delta (TCR‐δ) constant (C) regions with Ig heavy chain (H) variable (V) segments or TCR‐associated Ig‐like V (TAILV) segments to form chimeric IgV‐TCR, and combine TCRδC with both Ig‐like and TCR‐like V segments to form the doubly rearranging NAR‐TCR. Activation‐induced (cytidine) deaminase‐catalyzed somatic hypermutation (SHM), typically used for B‐cell affinity maturation, also is used by TCR‐α 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 (TCRαδV) segments using TCR αC but not δC. Second, mutation to IgHV segments associated with TCR δC was reduced compared to mutation to TCR αδV associated with TCR αC. Mutation was present but limited in V segments of all other TCR chains including NAR‐TCR. Unexpectedly, we found preferential rearrangement of the noncanonical IgHV‐TCRδC over canonical TCR αδV‐TCRδC receptors. The differential use of SHM may reveal how activation‐induced (cytidine) deaminase targets V regions.

Evolution of immunogenetic components encoding ultralong CDR H3

“…Chickens, which undergo a single VDJ recombination event, utilize AID-mediated somatic gene conversion to generate diversity, whereby portions of gene sequences from upstream pseudogenes replace homologous sequences in the recombined variable region (de los Rios et al 2015 ; Ratcliffe 2006 ). Sharks and camelids diversify T cell receptors (TCR) by incorporating AID-mediated somatic mutations during thymic development, likely to salvage receptors that otherwise would fail selection (Antonacci et al 2011 ; Chen et al 2012 ; Ciccarese et al 2014 ; Ott et al 2018 , 2020 ). Finally, lamprey and hagfish utilize AID-like enzymes (CD1/CD2) to somatically rearrange variable lymphocyte receptor (VLR) loci to create diverse lymphocyte receptors (Mitchell and Criscitiello 2020 ; Pancer et al 2004 , 2005 ).…”

Evolutionary Comparative Analyses of DNA-Editing Enzymes of the Immune System: From 5-Dimensional Description of Protein Structures to Immunological Insights and Applications to Protein Engineering

“…Due to CDA1/1L genes lacking introns, it has been posited that CDA2 was the original enzyme in all three lamprey lineages, with the ability to somatically diversify all three VLRs, and that CDA1/1L genes were the result of retrotransposon events after which CDA2 was subsequentially silenced in CDA1/1L + cell lineages. This idea is supported by the fact that in the first-diverged subsequent jawed vertebrate, the shark, AID appears to initiate somatic hypermutation of both B and T cell receptors (19,35,151,152). This suggests that perhaps this broader dual role of AID was lost in subsequent vertebrate lineages and the role became focused on antibody diversification in B cells only but the dual role appears again in limited later-diverged species, such as the Ballan Rasse (ray-finned fish) and in camels (36,153).…”

Evolution of surrogate light chain in tetrapods and the relationship between lengths of CDR H3 and VpreB tails

“…Further, we found that cytoplasmic tail regions in sequences from non-eutherian mammals were shorter and contained fewer (and in some cases no) proline residues, which in mice and humans are important for pre-TCR signaling and T cell development (Supplementary Figure 5) (61,62). This suggests that T cells of early tetrapods (and likely non-tetrapod jawed vertebrates) may use altered approaches to ensure functionality of their TCR, perhaps employing strategies like somatic hypermutation to further diversify receptors during T cell development in the thymus (as observed in nurse sharks) (63,64).…”