Cytomegalovirus Reinfections Stimulate CD8 T-Memory Inflation

Abstract

Cytomegalovirus (CMV) has been shown to induce large populations of CD8 T-effector memory cells that unlike central memory persist in large quantities following infection, a phenomenon commonly termed “memory inflation”. Although murine models to date have shown very large and persistent CMV-specific T-cell expansions following infection, there is considerable variability in CMV-specific T-memory responses in humans. Historically such memory inflation in humans has been assumed a consequence of reactivation events during the life of the host. Because basic information about CMV infection/re-infection and reactivation in immune competent humans is not available, we used a murine model to test how primary infection, reinfection, and reactivation stimuli influence memory inflation. We show that low titer infections induce “partial” memory inflation of both mCMV specific CD8 T-cells and antibody. We show further that reinfection with different strains can boost partial memory inflation. Finally, we show preliminary results suggesting that a single strong reactivation stimulus does not stimulate memory inflation. Altogether, our results suggest that while high titer primary infections can induce memory inflation, reinfections during the life of a host may be more important than previously appreciated.

The (gradual) rise of memory inflation

“…The cell phenotype is once again tightly maintained. Data with similar implications are obtained by experiments in the MCMV model, where the populations expanded by low‐dose infection can be further boosted (and driven toward a more differentiated phenotype) in response to reinfections 49, 68, 69…”

Cytomegalovirus immunoglobulin G titers do not predict reactivation risk in immunocompetent hosts

“…We and others have observed that mice infected with varying doses of mCMV develop variable mCMV‐specific antibody responses . Given the variability in tissue viral loads, we hypothesized that viral antibody responses might be used as a surrogate of underlying tissue viral loads.…”

“…Such tissue‐based studies are lacking, likely because the determination of tissue viral load requires invasive biopsies. Recent work has suggested that differing infectious titers induce different tissue viral loads and correspondingly proportional immune responses . This led us to hypothesize that serum IgG, which seems proportional to the magnitude of primary infection and ensuing tissue viral load, might be useful in predicting those patients with higher tissue viral loads and thus at greatest risk of reactivation.…”

NK cell and Th17 responses are differentially induced in murine cytomegalovirus infected renal allografts and vary according to recipient virus dose and strain

“…Thus, all D+ donor kidneys had the same virus strain and dose, whereas recipient infection conditions differed for each experimental group. All mice were infected >12 weeks prior to transplant to establish antiviral NK and CD8+ T cell memory (31, 37, 38). Uninfected mice were used for D−/R− transplants.…”