Naive T Cell Functional Heterogeneity

Abstract

Naive T cells are recently shown to be a heterogeneous compartment of cells with distinct phenotypical, regulatory, and functional characteristics. Currently, little is known in regards to their functional characteristics prior to antigen stimulation and their involvement in anti-tumor immunity. This dissertation aims to understand the contributions of naïve T cells to tumor immunity. The first project explores CXCL8+ naïve T cells in humans and how they can promote tumorigenesis. We found naïve T cells express CXCL8 without prior stimulation, and are primed for CXCL8 expression upon activation as compared to memory T cells and other effector cytokines. We suggest CXCL8+ naïve T cells may be important for tumorigenesis as co-injection of naïve T cells with cancer cells in a mouse model promotes tumor cell growth in a CXCL8-depenedint manner. The second project studies distribution of CD28H, a novel B7-family member, and the functional state at which naïve and memory T cells find themselves in adult peripheral blood, ovarian cancer patient blood and multiple tumors. CD28H was detected on T cells, primarily on naïve T cells, innate lymphoid cells (ILCs), natural killer (NK) cells, and plasmacytoid dendritic cells (PDCs). We found that CD28H marks undifferentiated T cells with lower effector function and suggest a potential role of CD28H shaping innate and adaptive immunity. The third project studies the consequences of loss of Dot1L in T cell phenotype, function and gene regulatory networks. Loss of Dot1L led to loss of naïve T cells in the periphery, increased apoptosis due to decreased STAT5 signaling and decreased cell cycle progression. Furthermore, Dot1L-deficeint T cells showed decreased anti-tumor and effector functions in vivo and in vitro. Very little is known regarding naïve T cells in the tumor microenvironment due in part to their discreet intra-tumoral numbers. Here we explore how naïve T cells promote tumor growth and their differentiation state in various tumors. Lastly, we show Dot1L is important for T cell homeostasis and function.