Memory CD8+ T Cells Remain Functional throughout an Ongoing Persistent Infection: Implications for Antigen-Specific Immune Reconstitution and Boosting

Cytomegalovirus (CMV) is a β-herpesvirus that establishes a persistent latent infection in a large percentage of the population. CMV stochastically but continuously reactivates from latency, and CMV-specific CD8+ T cells help maintain latency and prevent disease. Indeed, these reactivations drive the accumulation of certain CMV-specific CD8 + T cells over time (i.e. memory inflation). The majority of “inflationary” CD8+ T cells are terminally differentiated and have a defined half-life. However, a small subset of inflationary CD8+ T cells retain a memory-like phenotype (TM cells). It is unknown if these TM cells retain memory function. Loss of CMV-specific immunity is a major risk factor for developing CMV disease. Thus, CMV is a clinical concern in therapies that require immune suppression, including hematopoietic stem cell transplantation (HSCT). As such, immune reconstitution following HSCT remains a primary clinical objective. The goals of this dissertation are to utilize the mouse model of CMV (MCMV) to further our understanding of CMV immunity in the context of adoptive immunotherapy. First, we wanted to determine if the TM cells are more capable of reconstituting CMV immunity after adoptive transfer. By directly rechallenging the TM cells in various adoptive transfer scenarios, we demonstrate that the TM cells retain the ability to proliferate, differentiate and undergo inflation. In addition, we developed a novel transfer model and clearly showed that transferred TM cells can persist for weeks in a latently infected recipient and begin proliferating immediately if recipient immunity was lost. Secondly, we wanted to determine if administration of soluble MCMV peptides in vivo could induce proliferation of MCMV-specific CD8+ T cells. Indeed, administration of intravenous soluble peptide alone induced an expansion of peptide-specific CD8+ T cell populations in MCMV latently infected mice. Interestingly, this proliferation occurred regardless of the population’s initial dominance. Importantly, following peptide treatment, the peptide-specific CD8+ T cells retained proliferative capacity, the ability to produce cytokines and the ability to form resident memory T cells. Together, the findings described in this dissertation have expanded our understanding of the maintenance and activation of immunity during persistent latent infection and hopefully contribute to the development of improved therapeutic strategies