In models of chronic viral infection such as HIV, the canonical markers of T cell senescence (CD57) and exhaustion (PD-1) have been assumed to be dichotomous, identifying distinct T cell populations. Here we show that for CMV, the historic assumption that expression of these molecules is mutually exclusive may not be universally true.

We have examined CD57 and PD-1 expression in both healthy controls (HC) and in BMT patients. As shown in Fig 1A, we find that HCs that are CMV seropositive, and that respond robustly to CMV in vitro, can contain a population of CD8+ and CD4+ T cells that are double-positive for both CD57 and PD-1 (Fig 1A-B). CD57+/PD-1+ CD8 cells are predominantly Effector Memory (EM) cells (60%) and Effector Memory RA cells (32%), and CD57+/PD-1+ CD4 T cells are almost exclusively EM, (94% vs 3% TEMRA, 0.07% Naive and 2.8% TCM), consistent with their association with previous antigen exposure. Importantly, although previous work in HIV has suggested that PD-1+ cells are exhausted, and not capable of polyfunctionality, we observed that CD57+/PD-1+ double-positive CD8+ T cells are capable of producing both IFN-g and TNF when stimulated with CMV peptides (Fig 1C).

We have further characterized this T cell population in BMT patients, and find that those who reactivate CMV preferentially expand CD57+/PD-1+ T cells (Fig 2A). As in the HC, the PD-1+/CD57+ double positive cells in BMT patients were capable of producing both IFNg and TNF after a CMV peptide challenge. (Fig 2B).

Together, these results provide a novel mechanistic link between CMV infection and dual expression of CD57 and PD-1, suggesting that the historical view of dichotomous expression of these proteins may not be universally accurate. Functional analysis of this unique cell population, and its relation to anti-viral and alloreactive immunity post-transplant thus represents an important area for future investigation.

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