Lost structural and functional inter-relationships between Ig and TCR loci in mammals revealed in sharks

Abstract

Immunoglobulins and T cell receptors (TCR) have obvious structural similarities as well as similar immunogenetic diversification and selection mechanisms. Nevertheless, the two receptor systems and the loci that encode them are distinct in humans and classical murine models, and the gene segments comprising each repertoire are mutually exclusive. Additionally, while both B and T cells employ recombination-activating genes (RAG) for primary diversification, immunoglobulins are afforded a supplementary set of activation-induced cytidine deaminase (AID)-mediated diversification tools. As the oldest-emerging vertebrates sharing the same adaptive B and T cell receptor systems as humans, extant cartilaginous fishes allow a potential view of the ancestral immune system. In this review, we discuss breakthroughs we have made in studies of nurse shark (Ginglymostoma cirratum) T cell receptors demonstrating substantial integration of loci and diversification mechanisms in primordial B and T cell repertoires. We survey these findings in this shark model where they were first described, while noting corroborating examples in other vertebrate groups. We also consider other examples where the gnathostome common ancestry of the B and T cell receptor systems have allowed dovetailing of genomic elements and AID-based diversification approaches for the TCR. The cartilaginous fish seem to have retained this T/B cell plasticity to a greater extent than more derived vertebrate groups, but representatives in all vertebrate taxa except bony fish and placental mammals show such plasticity.

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Funding

This work was supported by grants from the NIH to MFC (AI56963) and MFF (AI027877 and AI140326) and the NSF to MFC (IOS-1257829 and IOS-1656870).

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Ott, J.A., Ohta, Y., Flajnik, M.F. et al. Lost structural and functional inter-relationships between Ig and TCR loci in mammals revealed in sharks. Immunogenetics 73, 17–33 (2021). https://doi.org/10.1007/s00251-020-01183-5

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Keywords

  • Immunoglobulins
  • T cell receptors
  • evolution: antigen receptor loci
  • activation induced cytidine deaminase
  • Shark
  • Vertebrate adaptive immune system
  • Bony fish
  • Placental mammals