During human and murine cytomegalovirus (MCMV) infection an exceptionally large virus-specific CD8 T cell pool is maintained in the periphery lifelong. This anomalous response is only seen for specific subsets of MCMV-specific CD8 T cells which are referred to as 'inflationary T cells'. How memory CD8 T cell inflation is induced and maintained is unclear, though their activated phenotype strongly suggests an involvement of persistent antigen encounter during MCMV latency. To dissect the cellular and molecular requirements for memory CD8 T cell inflation, we have generated a transgenic mouse expressing an MHC class I-restricted T cell receptor specific for an immunodominant inflationary epitope of MCMV. Through a series of adoptive transfer experiments we found that memory inflation was completely dependent on antigen presentation by non-hematopoietic cells, which are also the predominant site of MCMV latency. In particular, non-hematopoietic cells selectively induced robust proliferation of inflationary CD8 T cells in lymph nodes, where a majority of the inflationary CD8 T cells exhibit a central-memory phenotype, but not in peripheral tissues, where terminally differentiated inflationary T cells accumulate. These results indicate that continuous restimulation of central memory CD8 T cells in the lymph nodes by infected non-hematopoietic cells ensures the maintenance of a functional effector CD8 T pool in the periphery, providing protection against viral reactivation events.
Cytomegaloviruses (CMVs) infect the majority of the human population and persist lifelong via latency. CMV latency is thought to be a dynamic state, characterized by stochastic viral reactivation events coupled to CMV-derived antigen presentation. In support of this hypothesis is the exceptionally large CMV-specific CD8 T cell response which constitutes an integral part of immune surveillance of CMV reactivation. Conversely, it may also contribute to immune senescence as it significantly shapes the overall CD8 T cell pool in bias of CMV-specificity. In mice, only a subset of CMV-specific CD8 T cells, also called ‘inflationary CD8 T cells’, contribute to this large response. The mechanism leading to the selective accumulation and persistence of memory CD8 T cells during MCMV latency is largely unknown. Here, we unraveled the mechanisms of memory CD8 T cell inflation using a newly generated TCR transgenic mouse with specificity for an immunodominant inflationary MCMV epitope. We show that antigen presentation on non-hematopoietic cells is essential for memory inflation and that memory inflation in peripheral tissues is fueled by lymph node-resident central memory CD8 T cells, being locally reactivated by non-hematopoietic cells, inducing their local expansion and migration to peripheral tissues where they control viral reactivation events.