Somatic hypermutation of T cell receptor α chain contributes to selection in nurse shark thymus.

Jeannine A Ott,Michael F Criscitiello,Martin F Flajnik,Yuko Ohta,Thaddeus C Deiss,Caitlin D Castro

doi:10.7554/elife.28477

Jeannine A Ott, Michael F Criscitiello + Show 4 more

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https://doi.org/10.7554/elife.28477

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Journal: eLife	Publication Date: Apr 17, 2018
Citations: 33	License type: CC BY 4.0

Affiliation: Texas A&M University, University of Maryland, Baltimore

Abstract

Since the discovery of the T cell receptor (TcR), immunologists have assigned somatic hypermutation (SHM) as a mechanism employed solely by B cells to diversify their antigen receptors. Remarkably, we found SHM acting in the thymus on α chain locus of shark TcR. SHM in developing shark T cells likely is catalyzed by activation-induced cytidine deaminase (AID) and results in both point and tandem mutations that accumulate non-conservative amino acid replacements within complementarity-determining regions (CDRs). Mutation frequency at TcRα was as high as that seen at B cell receptor loci (BcR) in sharks and mammals, and the mechanism of SHM shares unique characteristics first detected at shark BcR loci. Additionally, fluorescence in situ hybridization showed the strongest AID expression in thymic corticomedullary junction and medulla. We suggest that TcRα utilizes SHM to broaden diversification of the primary αβ T cell repertoire in sharks, the first reported use in vertebrates.

Highlights

All jawed vertebrates share fundamental components of the adaptive immune system
Somatic mutations occur in rearranged variable regions of B cells responding to antigen at rates of 10 3 mutations per base pair per cell division (Odegard and Schatz, 2006)
These changes are dominated by point mutations, biased toward transitions (G:A and C:T), and preferentially targeted to the activation-induced cytidine deaminase (AID) motifs DGYW/WRCH (Li et al, 2004; Malecek et al, 2005; Odegard and Schatz, 2006; Rogozin and Diaz, 2004)

Summary

Introduction

All jawed vertebrates share fundamental components of the adaptive immune system. The cartilaginous fish (including sharks) are the most divergent jawed vertebrate group relative to mammals and use a polymorphic major histocompatibility complex (MHC) (Kasahara et al, 1992), multiple isotypes of immunoglobulin (Ig) heavy and light chains (Flajnik, 2002; Criscitiello and Flajnik, 2007), and the typical four T-cell receptor (TcR) chains (Rast et al, 1997). Shark lymphocyte antigen receptors are diversified by RAG-mediated V(D)J somatic rearrangement (Bernstein et al, 1994). B cells use the enzyme activation-induced cytidine deaminase (AID) for receptor modification via somatic hypermutation (SHM) (Conticello et al, 2005), allowing activated B cells to extensively alter their rearranged Ig variable region genes (Muramatsu et al, 2000). In addition to SHM in all jawed vertebrate Igs, AID catalyzes the processes of heavy chain class switch recombination (CSR) in tetrapods (and is implicated in shark CSR [Zhu et al, 2012]) and Ig gene conversion (in birds and some mammals) (Barreto and Magor, 2011). AID is a member of the APOBEC family of nucleic acid mutators, two of which likely diversify the variable lymphocyte receptor (VLR) system in the more ancient vertebrate lineages of lamprey and hagfish (Alder et al, 2005; Guo et al, 2009)

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