Abstract
With age, the immune system becomes less effective, causing increased susceptibility to infection. Chronic CMV infection further impairs immune function and is associated with increased mortality in the elderly. CMV exposure elicits massive CD8+ T cell clonal expansions and diminishes the cytotoxic T cell response to subsequent infections, leading to the hypothesis that to maintain homeostasis, T cell clones are expelled from the repertoire, reducing T cell repertoire diversity and diminishing the ability to combat new infections. However, in humans, the impact of CMV infection on the structure and diversity of the underlying T cell repertoire remains uncharacterized. Using TCR β-chain immunosequencing, we observed that the proportion of the peripheral blood T cell repertoire composed of the most numerous 0.1% of clones is larger in the CMV seropositive and gradually increases with age. We found that the T cell repertoire in the elderly grows to accommodate CMV-driven clonal expansions while preserving its underlying diversity and clonal structure. Our observations suggest that the maintenance of large CMV-reactive T cell clones throughout life does not compromise the underlying repertoire. Alternatively, we propose that the diminished immunity in elderly individuals with CMV is due to alterations in cellular function rather than a reduction in CD8+ T cell repertoire diversity.
Highlights
A s we age, immune function declines, a phenomenon known as immunosenescence
To determine the impact of large T cell clones on the peripheral blood T cell repertoire, we examined the repertoires of 543 CMVseropositive (CMV+) and CMV-seronegative (CMV2) subjects from a previous study [31]
Consistent with previous studies showing that CMV exposure induces massive T cell clonal expansions [40, 41], we found that the cumulative abundance of these large clones composed a significant proportion of the T cell repertoire in CMV+ compared with CMV2 individuals (p, 0.0005) in each age group (Fig. 1)
Summary
Large-scale changes in both the innate and adaptive immune system enhance susceptibility to infections and diminish responsiveness to vaccines, leading to increased morbidity and mortality [1,2,3,4]. Many of these changes are exacerbated by pathogens that lead to chronic or ORCIDs: 0000-0003-4392-1232 (P.L.); 0000-0002-7319-3371 (M.V.); 0000-00029570-2755 (E.H.W.); 0000-0002-4722-4461 (C.J.T.). M.V.G. and M.V. provided critical feedback and helped write the manuscript. C.J.T. designed and conducted the CMV stimulation assay and provided critical feedback on the results. H.S.R. designed and directed the study, provided critical feedback on the results, and helped write the manuscript. The relationship between CMV serostatus and mortality is thought to be the result of the large CMV-specific T cell response that develops postinfection and maintains the virus in a latent state
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
