In-Depth Profiling of T-Cell Responsiveness to Commonly Recognized CMV Antigens in Older People Reveals Important Sex Differences

Abstract

The impact of biological sex on T-cell immunity to Cytomegalovirus (CMV) has not been investigated in detail with only one published study comparing CMV-specific T-cell responses in men and women. Many studies, however, have shown an association between CMV infection and immunosenescence, with broad effects on peripheral blood lymphocyte subsets as well as the T and B-cell repertoires. Here, we provide a detailed analysis of CMV-specific T-cell responses in (n=94) CMV+ older people, including 47 women and 47 men aged between 60 and 93 years. We explore sex differences with respect to 16 different CMV proteins arranged in 14 peptide pools (overlapping peptides). Following ex vivo stimulation, CD4 and CD8 T-cells producing IFN-γ, TNF, and IL-2 were enumerated by flow-cytometry (intracellular cytokine staining). T-cell responses were evaluated in terms of each cytokine separately or in terms of cytokines produced simultaneously (polyfunctionality). Surface memory phenotype and CD3 downmodulation were assessed in parallel. The polyfunctionality index and a memory subset differentiation score were used to identify associations between response size, cytokine production, polyfunctionality, and memory subset distribution. While no significant sex differences were found with respect to overall CMV target protein selection, the T-cell response in men appeared more focused and accompanied by a more prominent accumulation of CMV-specific memory CD4 and CD8 T-cells. T-cell polyfunctionality and differentiation were similar in the sexes, however, CMV-specific T-cells in men produced more pro-inflammatory cytokines. Particularly, TNF production by CD4 T-cells was stronger in men than in women. Also, compared with women, men had larger responses to CMV proteins with immediate-early/early kinetics than women, which might have been driven by CMV reactivation. In conclusion, the CMV-specific T-cell response in men was larger and more pro-inflammatory than in women. Our findings may help explain sex differences in CMV-associated pathologies.

Aging beyond menopause selectively decreases CD8+ T cell numbers but enhances cytotoxic activity in the human endometrium

“…Senescent CD8+ T cells have enhanced cytotoxicity that could lead to increased pathology. Interestingly, Cytomegalovirus (CMV) infection (whose prevalence increases with age) has been associated with immunosenescence and with accumulation of T cells with high cytotoxic potential in peripheral blood, particularly in men [ 37 ]. The extent to which CMV infection may affect senescence of CD8+ T cells in the EM is completely unknown and would be an important aspect to address in the future.…”

How Can We Improve the Vaccination Response in Older People? Part II: Targeting Immunosenescence of Adaptive Immunity Cells

“…Concerning immune cell populations, epigenetics favour T and B lymphocyte activity in women, while myeloid function is favoured in men. Immunosenescence features are more pronounced in men, including CD4/CD8 ratio, telomere shortening, proportion of HCMV-specific memory cells and inflammaging [ 40 , 41 ]. In general, there is an increased infection/mortality ratio in men vs. women in infectious diseases.…”

Cytomegalovirus infection reduced CD70 expression, signaling and expansion of viral specific memory CD8+ T cells in healthy human adults

“…CMV infection induces differentiation of CMV-specific CD8 + T cells [ 12 ], which are responsible for containing CMV reactivation and the life-long interaction with CMV leads to significant expansion of CMV-specific effector memory CD8 + T cells in old humans [ 13 ]. Although human CMV has the largest genome of any known human virus, encoding over 162 potential proteins [ 14 , 15 ], the epitopes of CMV recognized by CD8 + T cells appear broad and display individual dominance associated with limited HLA haplotype (HLA-B7 and HLA-A2) [ 16 , 17 ]. CD8 + T cells that recognize an epitope of CMV phosphoprotein 65 (pp65 495–503 or NLVPMVATV) accounted for approximately 20% of total CD8 + T cell responses to CMV in HLA-A2 + subjects [ 17 , 18 ].…”