Analysis of macaque BTN3A genes and transcripts in the extended MHC: conserved orthologs of human \u03b3\u03b4 T cell modulators

Nanine De Groot,Gaby G M Doxiadis,Ronald E Bontrop,Rens Groen,Natasja G De Groot,Jesse Bruijnesteijn,Vaneesha Orie

doi:10.1007/s00251-019-01126-9

Nanine De Groot, Gaby G M Doxiadis + Show 5 more

Open Access

https://doi.org/10.1007/s00251-019-01126-9

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Abstract

Butyrophilins (BTN), specifically BTN3A, play a central role in the modulation of γδ T cells, which are mainly present in gut and mucosal tissues. BTN3A1 is known, for example, to activate Vγ9Vδ2 T cells by means of a phosphoantigen interaction. In the extended HLA region, three genes are located, designated BTN3A1, BTN3A2 and BTN3A3, which were also defined in rhesus macaques. In contrast to humans, rhesus monkeys have an additional gene, BTN3A3Like, which has the features of a pseudogene. cDNA analysis of 32 Indian rhesus and 16 cynomolgus macaques originating from multiple-generation families revealed that all three genes are oligomorphic, and the deduced amino acids display limited variation. The macaque BTN3A alleles segregated together with MHC alleles, proving their location in the extended (Major Histocompatibility Complex) MHC. BTN3A nearly full-length transcripts of macaques and humans cluster tightly together in the phylogenetic tree, suggesting that the genes represent true orthologs of each other. Despite the limited level of polymorphism, 15 Mamu- and 14 Mafa-BTN3A haplotypes were defined, and, as in humans, all three BTN3A genes are transcribed in PBMCs and colon tissues. In addition to regular full-length transcripts, a high number of various alternative splicing (AS) products were observed for all BTN3A alleles, which may result in different isoforms. The comparable function of certain subsets of γδ T cells in human and non-human primates in concert with high levels of sequence conservation observed for the BTN3A transcripts presents the opportunity to study these not yet well understood molecules in macaques as a model species.

Highlights

T cells are an essential component of the adaptive immune system and use cell surface bound receptors (TCRs) to recognize ligands that may signal the presence of intracellular infections or cellular stress
Molecules belonging to the butyrophilin (BTN) protein family, butyrophilin-3A (BTN3A), were identified as an essential component in the pAg activation pathway of Vγ9Vδ2 T cells (Abeler-Dorner et al 2012; Afrache et al 2012; Karunakaran and Herrmann 2014; Rhodes et al 2016; Vavassori et al 2013)
BTN3A genes belong to a multigene family, which maps in humans to the extended MHC class I region and comprises three genes: BTN3A1, BTN3A2 and BTN3A3 (Horton et al 2004; Rhodes et al 2001, 2016)

Summary

Introduction

T cells are an essential component of the adaptive immune system and use cell surface bound receptors (TCRs) to recognize ligands that may signal the presence of intracellular infections or cellular stress. Molecules belonging to the butyrophilin (BTN) protein family, butyrophilin-3A (BTN3A), were identified as an essential component in the pAg activation pathway of Vγ9Vδ2 T cells (Abeler-Dorner et al 2012; Afrache et al 2012; Karunakaran and Herrmann 2014; Rhodes et al 2016; Vavassori et al 2013). BTN3A proteins are cell-surface receptors expressed on a broad variety of cell types, including immune cells and some malignant cells such as ovarian cancer (Arnett and Viney 2014) They belong to the Ig-like superfamily and are evolutionarily and structurally related to the cluster of B7 costimulatory molecules CD80 and CD86 (Abeler-Dorner et al 2012; Afrache et al 2012; Rhodes et al 2016). A co-expression and multimerization of BTN3A1 with its sister molecules BTN3A2 and BTN3A3 may be necessary for their function, comparable to a concerted action as documented for other BTN molecules (Di Marco Barros et al 2016; Gu et al 2018; Rhodes et al 2015)

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