EPIGENETIC AND ENVIRONMENTAL MECHANISMS GOVERNING AUTOIMMUNE CD4+ T CELL PERSISTENCE

Abstract

Type 1 Diabetes (T1D) is an autoimmune disease mediated by the immune systems’ T cells destruction of insulin-producing β cells. T cells in autoimmunity can persist in the unfavorable conditions of chronic stimulation. In cancer and chronic infection, T cells become exhausted, however in autoimmunity they are less likely to become exhausted. T cell exhaustion has been defined in the context of TCF1 and Tox transcription factors, which are essential for T cell stemness and differentiation. Although it is established that CD8+ T cell exhaustion correlates with positive outcomes in autoimmunity; it remained unknown whether this is the final differentiation state for autoimmune CD4+ T cells. We showed that CD4+ T cells do not acquire signatures of T cell exhaustion as observed in chronic infection and cancer.

Type 1 Diabetes (T1D) is an autoimmune disease mediated by the immune systems’ T cells destruction of insulin-producing β cells. T cells in autoimmunity can persist in the unfavorable conditions of chronic stimulation. In cancer and chronic infection, T cells become exhausted, however in autoimmunity they are less likely to become exhausted. T cell exhaustion has been defined in the context of TCF1 and Tox transcription factors, which are essential for T cell stemness and differentiation. Although it is established that CD8+ T cell exhaustion correlates with positive outcomes in autoimmunity; it remained unknown whether this is the final differentiation state for autoimmune CD4+ T cells. We showed that CD4+ T cells do not acquire signatures of T cell exhaustion as observed in chronic infection and cancer. Further, CD4+ T cells activated in the absence of inflammatory signals maintained TCF1 expression, unlike activation during infection. CD4+ T cells recruited into the pancreas maintained TCF1 expression at later time points, even when new cell recruitment was blocked, suggesting permanent programming of stemness during autoimmunity. The Tcf7 locus, encodes TCF1, was epigenetically modified early in circulating autoimmune CD4+ T cells which were resembled in recently arrived, less differentiated CD4+ T cells within the pancreas. These data revealed that a unique environment during autoimmune CD4+ T cell priming allows T cells to fine-tune TCF1 expression and maintain long-term survival and pro-inflammatory function. We then dissected the role of T cell receptor (TCR) signals in supporting T cell persistence in the tissue. Pseudotime analysis revealed that CD4+ T cells differentiate into two trajectories distinguished based on the expression of IL-7 receptor (IL-7R) and Tfollicular-like (Tfh) phenotype with increased TCR signaling. TCR sequencing showed bifurcation of the two populations, indicating TCR-driven differentiation into distinct fates. Importantly, both populations were able to induce diabetes in mice. We predicted that persistence of both populations is maintained by distinct signals. IL-7R+ cells likely utilize IL-7 for survival, while Tfh-like phenotype could be maintained by interactions with B cells. Combining both IL-7R blockades with B cell depletion may target separate T cell populations and improve T1D therapeutic outcome.