Abstract
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.
Highlights
Memory CD8 T cells develop following primary encounter with an infectious agent and provide protection against subsequent infections
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
Summary
Memory CD8 T cells develop following primary encounter with an infectious agent and provide protection against subsequent infections Depending on their phenotype and anatomical location, memory CD8 T cells have been categorized into central memory CD8 T cells (TCM) and effector-memory CD8 T cells (TEM) [1,2]. TCM localize to secondary lymphoid organs due to expression of the lymph nodes homing markers CD62L and CCR7, and are maintained by homeostatic proliferation responding to the cytokines IL-7 and IL-15 [3,4] Because of their selfrenewal properties and their exquisite ability to proliferate and exert effector function upon re-encounter with the original pathogen, TCM are able to provide long-term protective immunity. Generation of memory responses are known to be highly perturbed during chronic or latent viral infections, where persistent antigen stimulation has often been shown to lead to functional impairment and antigen-dependent maintenance of CD8 T cells [13,14,15]
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