LAUSR

eBioMedicine 2022;77: 103887 Published online xxx https://doi.org/10.1016/j. ebiom.2022.103887 There is a widespread general consensus that protective immunity against infectious disease in older people is less effective than in younger adults, due to “immunosenescence”. There has been considerable controversy as to whether latent infection with human herpesviruses (HHV), particularly HHV5 (cytomegalovirus, CMV), seminally contributes to this state of immunosenescence. While it is clear that CMV-infected-vsnon-infected individuals display markedly different distributions of diverse immune cell phenotypes in the blood, the clinical implications of these findings remain unclear. In this issue, Nicoli et al. first provide confirmatory evidence from a wide-ranging cross-sectional study of 19 95-year olds that the number of CD8+ naÿve T cells is lower in the blood of older adults whether or not they are CMV-seropositive, but that lower numbers of naÿve CD4+ T cells in older adults are only seen in CMV-infected individuals. These findings are consistent with many published studies, but Nicoli et al. then proceed to test whether these and other differences are associated with the capacity of older adults to respond to antigens that they had not previously encountered, on the assumption that fewer naÿve CD4+ T cells would impair responsiveness. Paralleling the lower numbers of naÿve CD4+ T cells in these individuals, Nicoli et al. report that peak antibody titers after tick-borne encephalitis (TBE) vaccination were delayed and were lower in previously TBE-unexposed (i.e. antiTBE antibody-negative) CMV-seropositive relative to CMV-seronegative older adults. In vitro TBE-peptidestimulated CD4+ but not CD8+ T cell responses were also lower in CMV-seropositive individuals, in contract to memory T cell responses to HHV3 (Varicella Zoster, VZV) which were not different. These data provide circumstantial evidence that older adults exhibit blunted responses to neoantigens at least partially due to reductions in the numbers of naÿve T cells resulting in a shrunken T cell antigen receptor repertoire (which they documented by RNAseq) and this is exacerbated in