Herpesvirus-Specific CD8 T Cell Immunity in Old Age: Cytomegalovirus Impairs the Response to a Coresident EBV Infection

Abstract

Aging in humans is associated with increased infections and the reduced proliferative capacity of T cells, part of the more global phenomenon termed immune senescence. The etiology of immune senescence is unknown but the accumulation of virus-specific memory T cells may be a contributory factor. We have examined CD8 T cell responses to two persistent herpesvirus infections, CMV and EBV, and to a recurrent virus infection, influenza, in different age cohorts of healthy donors using HLA-peptide tetramers and intracellular cytokine detection. Of these, CMV appears to be the most immunogenic, with the CD8 T cell response representing over 10% of the CD8 pool in many elderly donors. Interestingly, the effect of age upon EBV-specific responses depends upon donor CMV sero-status. In CMV seropositive donors, the magnitude of the EBV-specific immune response is stable with age, but in CMV seronegative donors, the response to EBV increases significantly with age. By contrast, the influenza-specific CD8 T cell immune response decreases with age, independent of CMV status. The functional activity of the herpesvirus-specific immune response decreases in elderly donors, although the characteristic phenotypes of CMV- and EBV-specific memory populations are retained. This demonstrates that aging is associated with a marked accumulation of CMV-specific CD8 T cells together with a decrease in immediate effector function. Moreover, infection with CMV can reduce prevailing levels of immunity to EBV, another persistent virus. These results suggest that carriage of CMV may be detrimental to the immunocompetent host by suppressing heterologous virus-specific immunity during aging.

Differential Usage of Cellular Niches by Cytomegalovirus versus EBV- and Influenza Virus-Specific CD8+ T Cells

“…The fact that percentages decreased is explained by the increase in total CD8 ϩ T cells after infection with CMV. We thus confirm the finding by others that CMV infection leads to decreased percentages of EBV-specific cells in elderly individuals (19). However, the conclusion cannot be that EBV-specific CD8 ϩ T cells diminished in numbers.…”

The Context of Gene Expression Defines the Immunodominance Hierarchy of Cytomegalovirus Antigens

“…Experiments in the mouse model of infection with the murine CMV (MCMV) have shown that CMV-specific CD8 T cells accumulate in tissues (3) and in the blood (4) at times when the virus is latent, resulting in an ongoing expansion of CMV-specific T cells called "memory inflation" (4). Similarly, higher frequency of CMV-specific CD8 T cells could be observed with progressing age in blood samples of healthy humans (5), suggesting that HCMV-specific cellular immunity may similarly increase, or "inflate," with age.…”

Mouse CMV infection delays antibody class switch upon an unrelated virus challenge

“…CMV infection is associated with increased numbers of CD28-or CD45RA+ T-cells in both CD4 and CD8 subsets (Looney et al, 1999) in a manner that recapitulates the aging-related accumulation of these subsets (Chidrawar et al, 2009). CMV is also associated with functional immune deficits in the aging host, including lower counts of Epstein Barr Virus (EBV) specific CD8 T-cells (Khan et al, 2004), increased reactivation of varicella-zoster virus (Ogunjimi et al, 2013) or excess mortality (Roberts et al, 2010;Wikby et al, 2002), mainly due to vascular causes (Roberts et al, 2010;Savva et al, 2013).…”