Hematogenous maintenance of memory inflation and continuous production of mucosal resident T cells during murine cytomegalovirus (MCMV) infection
Viruses in the Herpesviradae family cause latent infections that require life-long immune control from the host to prevent disease. The β herpesvirus Cytomeglovirus (CMV) induces a CD8 T cell response that is maintained at unusually high levels for life in a process known as memory inflation. This response is known to be important in the control of virus, yet the mechanism that supports it is poorly understood. Here, we use murine cytomegalovirus (MCMV) to show that during memory inflation, MCMV-specific CD8 T cells undergo continuous turnover and are replenished by the continuous production of new short lived effectors. Previous studies have suggested that during MCMV latency, antigen in the lymph nodes drives the production of new inflationary effectors that migrate to latently infected organs to carry out immune surveillance. However blocking T cell egress from the lymph nodes with FTY720 had virtually no impact on the maintenance of memory inflation. Instead, intravascular staining showed that the primary site of effector division was in the blood or vasculature. Surprisingly, the defining characteristics of CD8 T cells undergoing memory inflation (i.e. effector phenotype and numerical dominance over non-inflationary populations) were only evident in the blood localized inflationary T cells. The MCMV-specific CD8 T cells that are localized in mucosal tissues primarily express high levels of CD69 and in some cases CD103, which are markers of tissue resident memory T cells. Adoptive transfer experiments show that most MCMV-specific TRM cells formed early after infection and that spleen-localized cells had reduced capacities to become TRM at late times. Surprisingly however, persistent antigen supported the continuous recruitment of small numbers of new TRM cells from the circulating CD8 pool throughout infection. This favors populations maintained at high levels in the blood and shifts the immunodominance within the TRM populations over time. Thus we have refined the model of CD8 T cell surveillance during latent infection, by showing that memory inflation is primarily confined to the blood while the mucosal sites that are critical in the persistence and spread of MCMV are inhabited by tissue resident T cells.
Smith, Corinne J, "Hematogenous maintenance of memory inflation and continuous production of mucosal resident T cells during murine cytomegalovirus (MCMV) infection" (2015). ETD Collection for Thomas Jefferson University. AAI3733953.