Ageing and latent CMV infection impact on maturation, differentiation and exhaustion profiles of T-cell receptor gammadelta T-cells

Ageing is a broad cellular process, largely affecting the immune system, especially T-lymphocytes. Additionally to immunosenescence alone, cytomegalovirus (CMV) infection is thought to have major impacts on T-cell subset composition and exhaustion. These impacts have been studied extensively in TCRa beta+T-cells, with reduction in naive, increase in effector (memory) subsets and shifts in CD4/CD8-ratios, in conjunction with morbidity and mortality in elderly. Effects of both ageing and CMV on the TCR gamma delta+ T-cell compartment remain largely elusive. In the current study we investigated V gamma-and V delta-usage, maturation, differentiation and exhaustion marker profiles of both CD4 and CD8 doublenegative (DN) and CD8+ TCR gamma delta+ T-cells in 157 individuals, age range 20-95. We observed a progressive decrease in absolute numbers of total TCR gamma delta+ T-cells in blood, affecting the predominant V gamma 9/V delta 2 population. Aged TCR gamma delta+ T-cells appeared to shift from naive to more (late-stage) effector phenotypes, which appeared more prominent in case of persistent CMV infections. In addition, we found effects of both ageing and CMV on the absolute counts of exhausted TCR gamma delta+ T-cells. Collectively, our data show a clear impact of ageing and CMV persistence on DN and CD8+ TCR gamma delta+ T-cells, similar to what has been reported in CD8+ TCR alpha beta+ T-cells, indicating that they undergo similar ageing processes.