Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion

Northwestern University At Chicago, Evanston IL

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Abstract

Summary Successful control of chronic viruses, such as HIV and HCV, critically depends on our improved understanding of the cellular and molecular mechanisms underlying T cell exhaustion. Notably, recent research underscores the importance of progenitor (TPRO) CD8 T cells in sustaining the CD8 T cell response during persistent antigen exposure by generation of terminally differentiated exhausted (TEXH) and effector (TEFF) subsets. However, little is known regarding the mechanisms governing TPRO cell formation and their ability to stay quiescent in the presence of persistent viral antigen and inflammation. During chronic viral infection, TPRO cells emerge early, similar to the formation of memory precursor cells (MPCs) during acute infection. These TPRO cells act as a lasting resource, replenish TEXH and TEFF populations at the late phase of chronic infection. Similarities in the development of TPRO and memory CD8 T cells suggest shared transcriptional and epigenetic mechanisms that govern the formation of both cell types. Consistently, several transcription factors (TFs) linked to memory T cell formation, like TCF-1, BACH2, and MyB, play essential roles in maintaining stem cell-like features in TPRO CD8 T cells during chronic infection and cancer. However, specific impact of epigenetic regulators on TPRO cell formation and function remains insufficiently explored, representing a significant gap in our knowledge. To bridge this gap and identify potential epigenetic regulators, the investigator’s team conducted single-cell RNA sequencing on virus-specific CD8 T cells and observed distinct expression of Satb1 in the TPRO subset. SATB1 is known for orchestrating epigenetic regulations controlling stem cell identity in multiple tissue-specific progenitor cells. This led them to investigate whether SATB1 regulates TPRO cell formation and maintains their stemness during chronic viral infection. Using CRISPR/Cas9 to directly delete Satb1 in virus-specific CD8 T cells, they found that SATB1-deficient CD8 T cells exhibited a reduced capacity to form or maintain the stemness of TPRO cells. Instead, they gave rise to more terminally differentiated TEFF and TEXH cells. This decrease in TPRO cells coincided with the loss of TCF-1 expression, a key TF essential for the stemness and self-renewal of progenitor and memory CD8 T cells. These findings suggest that SATB1 is necessary for the formation and/or maintenance of TPRO cells. Building on these observations, the investigator’s team hypothesize that SATB1 regulates the quiescence and stemness of progenitor cells for their formation, long-term maintenance, and function during chronic viral infection. They also propose that the SATB1-regulated progenitor program serves as a conserved mechanism applicable to memory CD8 T cell differentiation during acute viral and bacterial infections. They plan to test these hypotheses and further investigate how SATB1 mechanistically regulates key features of progenitor and memory cells, maintaining their versatile differentiation potential in the proposed competitive renewal.