Protection from microbial infections relies on both innate and adaptive immune responses. A critical feature of the adaptive immune response is the ability to form memory T and B cells that can protect from re-infection long-term. In particular, functional memory CD8 T cells can rapidly expand their numbers and produce anti-viral cytokines and cytotoxic molecules to help control secondary infections swiftly. Effective vaccines that can generate long-lived and functional memory T and B cells can offer life-saving protection against infectious disease (and perhaps even cancer), however, we do not clearly understand how functional memory T and B cells develop during a primary immune response. This broad goal of this proposal is to understand how differentiation of effector CD8 T cells is regulated, and how perturbations in effector cell differentiation affects formation of long-lived memory CD8 T cells during acute infection with lymphocytic choriomeningitis virus (LCMV), a category A NIAID pathogen. Specifically, we propose the model that during viral infection virus- specific effector CD8 T cells differentiate along a continuum of developmental stages and most cells eventually reach a terminally differentiated stage. Concomitant with reaching this endpoint, the proliferative capacity and longevity of the effector cells greatly declines and they lose the ability to become long-lived, protective memory CD8 T cells. To study this model, we have investigated the role of a transcriptional repressor B lymphocyte-induced maturation protein (Blimp-1) in effector and memory CD8 T cell development because this transcription factor is associated with terminal differentiation of multiple cell types including B cells. Our preliminary data demonstrate that Blimp-1 plays an important role in several facets of effector CD8 T cell differentiation and appears to regulate the formation of terminally differentiated effector cells during acute viral infection. Here, we aim to extend this investigation to determine if Blimp-1 regulates the functional capacity of memory CD8 T cells to be long-lived and protect against secondary infection. Furthermore, we explore how loss of Blimp-1 in CD8 T cells alters the function of its alter ego Bcl-6. Lastly, we investigate the signals that induce Blimp-1 expression in CD8 T cells to offer insight into factors that influence generation of memory CD8 T cells. The identification of key molecules that inhibit formation of memory CD8 T cells or their function are critical to improving our understanding of memory T cell development and creating improved vaccines and T cell-oriented therapies that enhance human health worldwide and defend against biowarfare attacks. ? ? ?
| Rutishauser, Rachel L; Martins, Gislâine A; Kalachikov, Sergey et al. (2009) Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31:296-308 |
| Kaech, Susan M; Wherry, E John (2007) Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity 27:393-405 |
