The Vγ2/Vδ2 T-cell repertoire in Macaca fascicularis: functional responses to phosphoantigen stimulation by the Vγ2/Jγ1.2 subset

Abstract

Circulating Vγ2/Vδ2 T cells in human and non-human primates respond to small molecular weight non-peptidic phosphoantigens in a major histocompatibility complex (MHC)-unrestricted manner. These responses are encoded by the Vγ2/Jγ1.2 chain of the T-cell receptor and are positively selected during early development to create a biased repertoire in adults. We characterized the Vγ2 chain in cynomolgus macaques (Macaca fascicularis) to develop a non-human primate model for studying the effects of infection and therapy on the circulating Vγ2/Vδ2 T-cell subset. The cynomolgus macaque Vγ2 chain was highly homologous to the Vγ2 chain from human beings and rhesus macaques (Macaca mulatta), though we noted conserved substitutions in critical residues within the CDR3 for both macaque species. Despite these substitutions, Vγ2/Vδ2(+) T cells from cynomolgus monkeys exhibited polyclonal responses to two different phosphoantigens. Proliferative responses were observed with both isopentenylpyrophosphate and alendronate, but stronger interferon-γ secretory responses were observed with isopentenylpyrophosphate. In vitro stimulation and expansion led to selective outgrowth of the Vγ2/Jγ1.2 subset, with a marked shift in the Vγ2 spectratype. As a result of the less biased starting repertoire for Vγ2, the cynomolgus macaque constitutes a sensitive model for examining the effects of in vitro or in vivo treatments on the Vγ2/Vδ2 T-cell population. Our studies establish the value of cynomolgus macaques as a model for Vγ2/Vδ2 T-cell responses to non-peptidic antigens, and further evidence the remarkable evolutionary conservation of this unusual, phosphoantigen-responsive T-cell subset that is found only in primate species