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

Circulating V gamma 2/V delta 2 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 V gamma 2/J gamma 1.2 chain of the T-cell receptor and are positively selected during early development to create a biased repertoire in adults. We characterized the V gamma 2 chain in cynomolgus macaques (Macaca fascicularis) to develop a non-human primate model for studying the effects of infection and therapy on the circulating V gamma 2/V delta 2 T-cell subset. The cynomolgus macaque V gamma 2 chain was highly homologous to the V gamma 2 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, V gamma 2/V delta 2(+) T cells from cynomolgus monkeys exhibited polyclonal responses to two different phosphoantigens. Proliferative responses were observed with both isopentenylpyrophosphate and alendronate, but stronger interferon-gamma secretory responses were observed with isopentenylpyrophosphate. In vitro stimulation and expansion led to selective outgrowth of the V gamma 2/J gamma 1.2 subset, with a marked shift in the V gamma 2 spectratype. As a result of the less biased starting repertoire for V gamma 2, the cynomolgus macaque constitutes a sensitive model for examining the effects of in vitro or in vivo treatments on the V gamma 2/V delta 2 T-cell population. Our studies establish the value of cynomolgus macaques as a model for V gamma 2/V delta 2 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.