Identification of novel mediators of T cell function in chronic infection and cancer

Abstract

Cytotoxic CD8⁺ T cells are critical mediators of immunity against chronic viral infection and cancer. However, when CD8⁺ T cells are persistently exposed to high amounts of antigen, they lose their functionality and differentiate into 'exhausted' T cells (T_EX). Hallmarks of exhaustion are high expression of inhibitory receptors, also called immune checkpoints, like PD-1, increased expression of TCR-responsive transcription factors like TOX, compromised cytokine production and diminished proliferative capacity. Previous studies by our group and others have shown that the pool of exhausted T cells contains functionally important subsets with distinct epigenetically and transcriptional profiles, including precursors of exhausted T cells (T_PEX). T_PEX display characteristics of both, exhausted and memory T cells. Furthermore, they include a population of stem-like cells, marked by the expression of CD62L and the transcription factor Myb, that mediates long term maintenance of CD8⁺ T cell immunity and response to PD-1 checkpoint inhibition by a proliferative burst. It was shown that T_PEX cells can differentiate into two distinct populations of T_EX, including CX3CR1⁺ effector-like cells and CD101⁺ terminally exhausted cells. The molecular mechanism that regulates and drive the differentiation of T_PEX and T_EX and thus giving rise to new targets of cancer therapy, are still not fully understood. In this thesis we identify SATB1 as a critical factor in T_PEX and T_EX differentiation. SATB1 deficiency accelerates T_EX formation in chronic infection and skews acute infection responses toward effector memory. It also regulates cytokine expression and PD-1 levels, making it a potential target for CAR-T therapies. Additionally, we show that migratory molecules (CD62L, CCR7, S1PR1) are crucial for T_PEX maintenance and T_EX generation. Their disruption primarily affects CX3CR1⁺ T_EX cells, highlighting the role of spatial organization in exhaustion regulation. Finally, we establish KLF2 as a key regulator controlling the development of CD62L⁺ T_PEX cells and their differentiation into CX3CR1⁺ T_EX cells. KLF2 loss enhances effector function but increases exhaustion markers. Notably, statins upregulate KLF2, suggesting a pharmacological approach to modulating exhaustion dynamics. These findings advance our understanding of CD8⁺ T cell differentiation and exhaustion, providing insights for improving immunotherapies in chronic infections and cancer.