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Abstract

ATF6α is an ER-stress sensor, which participates in the “Unfolded Protein Response” (UPR). Under conditions of infection, inflammation and cancer, ATF6α activation is found to be elevated in distinct subsets of T cells in preclinical models and human patients (unpublished data). Since T cell function is characterized by the secretion of cytokines - produced and maturated in the ER -, ER abnormalities might affect the character of T cells. Here, I show that T cell-specific hyperactivation of ATF6α leads to overproduction of cytotoxic cytokines, higher proliferation and enhanced differentiation into more active forms (effector and central memory T cells). This suggests that Atf6α could be a crucial component for the quality and strength of CD4- and CD8- downstream immune responses, expanding from humoral to cellular immunity. When interrogating the effect of Atf6α in humoral immunity, I observed preferential differentiation of Atf6α-overexpressing T cells into T follicular helper cells (Tfh), with concomitant elimination of the Treg subset. Thus, increased de novo formation of splenic germinal centers (GC) was induced in SPF mice lacking antigen-stimulation, suggesting a pivotal role of T cell-originated ATF6α activation in GC formation. In line, Atf6α deficiency compromised the germinal center establishment upon stimulation with Sheep Red Blood Cells (SRBC). Furthermore, I have explored the influence of differential Atf6α expression in cellular immune responses, specifically against viral infections (LCMV virus) and liver cancer. The viral infections have shown no significant results for the role of Atf6α in promoting T cell exhaustion in the context of chronic LCMV infection. Last, I investigated the competence of T cells with high ATF6α activation in the context of metabolic dysfunction-associated steatohepatitis (MASH) and subsequent live cancer: Mice with T cell-specific ATF6α activation, upon feeding with CD-HFD (choline-deficient high fat diet) for 12 months, are protected from hepatitis and liver cancer, when compared to their wild type littermates. Immunophenotyping of Atf6α overexpressing T cells, revealed an increase of the effector and central memory T cell subsets, accompanied by elevated secretion of cytotoxic cytokines. In contrast, mice devoid of ATF6α in their T cells, display increased liver cancer incidence, with concomitant upregulation of terminal exhaustion markers and Treg polarization. Overall, my findings suggest a hitherto unknown decisive role of Atf6α expression levels in T cells for the activation of humoral and cellular immune responses. In summary, ATF6α activation in T cells promotes increased differentiation into effector/ memory T cells and higher cytokine production, while preventing their immunosuppressive shift. These changes in the T cell character functionally control the formation and establishment of germinal centers, in the context of humoral immune response and a more effective immunosurveillance against MASH-HCC, in the context of cellular immune response, thus holding promise as a potential candidate for ameliorating anti-tumor efficacy of CAR T cells.