Naive CD8 T cell functional heterogeneity

Project Summary There has been considerable progress in identifying subsets in effector, memory, and exhausted CD8 T cells, and our understanding of the role of each subset in response to infection has greatly improved. However, much less is known about the heterogeneity of naïve CD8 T cells, the predecessors of these antigen-experienced T cells. We have recently tackled this important issue, and our preliminary data show that there is a naïve CD8 T cell population with a superior ability to generate more effector CD8 T cells after infection. A deeper understanding of the naïve CD8 T cell heterogeneity will help to develop strategies to produce just such a better naïve CD8 T cell population. Since naïve T cells have an enormous TCR repertoire diversity capable of recognizing virtually any non-self antigens including pathogens and tumor neoantigens, making a high-quality naïve T cell population that gives rise to potent effector and memory T cell responses would provide better protection against known and unknown pathogens, enhance responsiveness to existing vaccines, and even prevent the development of cancer. Our long-term objective is: To elucidate how naïve CD8 T cell heterogeneity is generated and maintained and to understand qualitative differences among naïve CD8 T cell subsets; Ultimately, to use this information to establish novel strategies to induce protective naïve CD8 T cell immunity against pathogens and cancer. Toward this objective, we will investigate both mouse and human naïve CD8 T cells. Our proposed studies in this application represent a new direction of research in the area of naïve CD8 T cell heterogeneity. The following specific aims are proposed: Specific Aim 1: To elucidate how naïve CD8 T cell heterogeneity contributes to immune response and homeostasis of T cells in mice. Specific Aim 2. To define human naïve CD8 T cell atlas by examining antigen specific CD8 T cells in the young and aged adults as well as newborns.