Cytomegalovirus drives Vδ2neg γδ T cell inflation in many healthy virus carriers with increasing age

Abstract

Cytomegalovirus (CMV) usually causes lifelong asymptomatic infection, but over time can distort immune profiles. Recent reports describe selective expansion of Vδ2neg γδ T cells in healthy and immunocompromised CMV carriers. Having shown previously that virus-specific CD8+ and CD4+ T cell responses are increased significantly in elderly CMV carriers, probably driven by chronic stimulation, we hypothesized that Vδ2neg γδ T cells may also be expanded with age. Our results show that Vδ2neg γδ T cells are increased significantly in CMV-seropositive healthy individuals compared to CMV-seronegative controls in all age groups. The differences were most significant in older age groups (P < 0·0001). Furthermore, while Vδ2neg γδ T- cells comprise both naive and memory cells in CMV-seronegative donors, highly differentiated effector memory cells are the dominant phenotype in CMV carriers, with naive cells reduced significantly in numbers in CMV-seropositive elderly. Although phenotypically resembling conventional CMV-specific T cells, Vδ2neg γδ T cells do not correlate with changes in magnitude of CMV-specific CD4+ or CD8+ T cell frequencies within those individuals, and do not possess ex-vivo immediate effector function as shown by CMV-specific CD4+ and CD8+ T cells. However, after short-term culture, Vδ2neg γδ T cells demonstrate effector T cell functions, suggesting additional requirements for activation. In summary, Vδ2neg γδ T cells are expanded in many older CMV carriers, demonstrating a further level of lymphocyte subset skewing by CMV in healthy individuals. As others have reported shared reactivity of Vδ2neg γδ T cells towards tumour cells, the composition of γδ T cell subsets may also have implications for risk of developing cancer in elderly people.