Evidence for somatic hypermutation at shark T cell receptor α locus (43.6)

Abstract

Somatic hypermutation (SHM) is a mechanism B cells use while responding to antigen for affinity maturation, and is also employed in the diversification of the primary B cell repertoire in the gut associated lymphoid tissues of ruminants. Recently it was discovered that SHM operates at the T cell receptor γ locus of the sandbar shark. We have looked for evidence of this AID-mediated mechanism at other T cell receptor loci in the nurse shark, Ginglymostoma cirratum. Our initial hypothesis invoked SHM at the γ and δ loci, but not at the (presumably) MHC-restricted α and β loci. Surprisingly, we find evidence for mutation at the α locus. We see evidence for canonical point mutations as well as the tandem mutations that have been a hallmark of SHM at traditional immunoglobulin, IgNAR and now T cell receptor loci of cartilaginous fish. Ongoing studies are assaying SHM at α in the shark thymus to determine if this phenomenon is being employed for affinity maturation of αβ T cell responses (a process we deem unlikely with MHC restriction). Alternatively, SHM may be used along with receptor editing at the α locus in the thymus to generate primary repertoire paratopes that can mutate to positive selection. The thymus was suggested as a “mutant breeding” organ for self tolerance by Neils Jerne forty years ago - future comparative studies will determine if SHM is an original tool of vertebrate T cells for thymic diversification or an adaptation singular to sharks.