Summary During persistent murine cytomegalovirus (MCMV) infection the T cell response is maintained at extremely high levels for the life of the host. These cells closely resemble human CMV-specific cells which comprise a major component of the peripheral T cell compartment in most people. Despite a phenotype that suggests extensive antigen-driven differentiation, MCMV-specific T cells remain functional and respond vigorously to viral challenge. We hypothesized that a low rate of antigen-driven proliferation would account for the maintenance of this population. Instead, we found that most of these cells divide only sporadically in chronically infected hosts and have a short half-life in circulation. The overall population is supported, at least in part, by memory cells primed early in infection as well as recruitment of naïve T cells at late times. These data show that memory inflation is maintained by a continuous replacement of short-lived, functional cells during chronic MCMV infection.

Central tolerance is established through negative selection of self-reactive thymocytes and the induction of T-regulatory cells (T R s). The role of thymic dendritic cells (TDCs) in these processes has not been clearly determined. In this study, we demonstrate that in vivo , TDCs not only play a role in negative selection but in the induction of T R s. TDCs include two conventional dendritic cell (DC) subtypes, CD8 lo Sirpα hi/+ (CD8 lo Sirpα + ) and CD8 hi Sirpα lo/− (CD8 lo Sirpα − ), which have different origins. We found that the CD8 hi Sirpα + DCs represent a conventional DC subset that originates from the blood and migrates into the thymus. Moreover, we show that the CD8 lo Sirpα + DCs demonstrate a superior capacity to induce T R s in vitro . Finally, using a thymic transplantation system, we demonstrate that the DCs in the periphery can migrate into the thymus, where they efficiently induce T R generation and negative selection.

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Cytotoxic lymphocytes express a large family of granule serine proteases, including one member, granzyme (Grz)M, with a unique protease activity, restricted expression, and distinct gene locus. Although a number of Grzs, including GrzM, have been shown to mediate target cell apoptosis in the presence of perforin, the biological activity of Grz has been restricted to control of a number of viral pathogens, including two natural mouse pathogens, ectromelia, and murine CMV (MCMV). In this article, we describe the first reported gene targeting of GrzM in mice. GrzM-deficient mice display normal NK cell/T cell development and homeostasis and intact NK cell-mediated cytotoxicity of tumor targets as measured by membrane damage and DNA fragmentation. GrzM-deficient mice demonstrated increased susceptibility to MCMV infection typified by the presence of more viral inclusions and transiently higher viral burden in the visceral organs of GrzM-deficient mice compared with wild-type (WT) mice. The cytotoxicity of NK cells from MCMV-infected GrzM-deficient mice remained unchanged and, like WT control mice, GrzM-deficient mice eventually effectively cleared MCMV infection from the visceral organs. In contrast, GrzM-deficient mice were as resistant as WT control mice to mouse pox ectromelia infection, as well as challenge with a number of NK cell-sensitive tumors. These data confirm a role for GrzM in the host response to MCMV infection, but suggest that GrzM is not critical for NK cell-mediated cytotoxicity.

Central tolerance is established through the negative selection of self-reactive thymocytes and the induction of T-regulatory cells (T-regs). A role for thymic epithelial cells in mediating both negative selection and T-reg induction has been clearly shown. The role of thymic dendritic cells (DCs) in these processes has not been clearly determined but has been the focus of recent studies. Thymic DCs include two conventional DC (cDC) subtypes, CD8 lo Sirpa hi/+ (CD8 lo Sirpa + herein) and CD8 hi Sirpa lo/À (CD8 hi Sirpa À herein). It has been shown that these DC subsets have distinct developmental origins, the CD8 hi Sirpa À cDCs developing intra-thymically and the CD8 lo Sirpa + migrating into the thymus from the periphery. Furthermore, an important role for thymic DCs in the induction of T-regs has been shown. In this review, the role of DCs in the development and education of T cells in the thymus will be reviewed, with emphasis on the role of circulatory DCs in mediating these processes.