CD8+ T cells integrate signals from the T cell receptor, co-stimulatory molecules, and cytokines that control their clonal expansion and differentiation into specialized populations of terminal effector cells or long-lived memory cells. Although the generation of effector and memory CD8+ T cells is required for clearance of intracellular infections and forms the basis for vaccination strategies against a wide-range of pathogens and anti-cancer immunotherapy, CD8+ T cells can also cause autoimmune tissue damage, and are a barrier to effective tissue transplantation. Thus, understanding the molecular control of CD8+ T cell expansion, differentiation and function will have wide-ranging applications in manipulating CD8+ T cell responses in the contexts of vaccination and infectious disease, autoimmunity, transplantation and tumor immunotherapy. However, despite extensive study our knowledge of the key molecules that direct the differentiation, function and homeostasis of different populations of effector and memory CD8+ T cells remains incomplete. We have made the novel observation that the signaling adaptor BCAP is rapidly upregulated upon activation of CD8+ T cells. Moreover, we show that loss of BCAP impairs normal clonal expansion of CD8+ T cells and alters effector/memory cell differentiation. Thus, we have identified BCAP as a critical and previously uncharacterized signaling hub that helps control the outcome of CD8+ T cell activation. Thus, better understanding BCAP function and identifying its associated signaling pathways will help define the molecular basis for CD8+ T cell function, and provide new targets for therapeutically manipulating of CD8+ T cell responses. In this proposal, we will build on these exciting preliminary studies to comprehensively determine how BCAP-dependent signaling impacts the proliferation, differentiation and function of effector and memory CD8+ T cells, and to define the key molecular pathways regulated by BCAP that help control each of these processes.
The generation of effector and memory CD8+ T cells is required for clearance of intracellular pathogens and forms the basis for vaccination strategies against a wide range of pathogens and anti-cancer immunotherapy. CD8+ T cells can also cause autoimmune tissue damage, and are a barrier to effective tissue transplantation. Therefore, defining the key molecular pathways that control CD8+ T cell responses will help identify new targets for manipulating these responses in a wide range of immunological diseases. The overall goal of this proposal is to determine how the signaling adaptor BCAP influences the generation and function of effector and memory CD8+ T cells.
|Singh, Mark D; Ni, Minjian; Sullivan, Jenna M et al. (2018) B cell adaptor for PI3-kinase (BCAP) modulates CD8+ effector and memory T cell differentiation. J Exp Med 215:2429-2443|
|Newton, Ryan H; Shrestha, Sharad; Sullivan, Jenna M et al. (2018) Maintenance of CD4 T cell fitness through regulation of Foxo1. Nat Immunol 19:838-848|