Deciphering the developmental requirements of CD4+ tissue-resident memory T cells

• Applicant: Dr. Tobias Poch
• Subject Area: Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508403993

Only a decade ago, T cells residing within peripheral tissues, i.e. tissue-resident memory T cells (TRM), were found to be a distinct subset of T cells that substantially differ from their circulating counterparts. Since then, both CD4+ and predominantly CD8+ TRM have been identified within a range of organs and epithelial sites in both humans and mice, where their presence has been correlated with improved disease outcomes in a number of settings. As CD8+ T cells are the predominant subset establishing this phenotype, many details on CD8+ TRM differentiation have already been revealed. However, the rules governing CD4+ T cell tissue residency are less clear. Key phenotypical features of CD4+ TRM appear to be partly similar to CD8+ TRM and hypotheses on common transcriptional events were formulated. However, CD4+ TRM biology is a so far understudied topic resulting in lack of hard evidence addressing these hypotheses. CD4+ TRM cells are of rising interest, as they differ in function and localization from CD8+ TRM. However, the cytokines guiding CD4+ T cells to tissues and which specific CD4+ subset, if there is any, gives rise to CD4+ TRM remains unknown. As there is range of different CD4+ T cell subsets and polarization states, it has even been speculated on that there is a specific CD4+ TRM precursor different from the other main CD4+ subsets. In preliminary work, the existence of CD4+ T cells that acquired tissue residency, although displaying a naive phenotype, was revealed in the settings of primary sclerosing cholangitis, a rare autoimmune liver disease. This finding is in line with the unknowns mentioned above and leads us to the hypothesis that CD4+ T cells can enter and reside in non-lymphoid tissues, independent of their TH-polarization and state of differentiation, when specific transcriptional requirements are met. We will test this hypothesis by analyzing acute and memory phases of infection in mice using state-of-the-art full spectrum flow cytometry, different single-cell sequencing methods and CRISPR/Cas9 gene editing. Mechanistic insights will be validated in human CD4+ T cells from peripheral blood and various tissues. As more than 95 % of T cells reside within tissue, it is essential to study the mechanisms of both how T cells adapt to certain environments within tissues and how T cells function within a specific tissue. Our findings will contribute to better understanding of these fundamental mechanisms of tissue immunity, which, in a long-term perspective, will pave the way for specific treatment options in e.g. immune-mediated diseases as well as improve vaccination strategies to provide long-lasting immunity against infectious diseases.

• DFG Programme: WBP Fellowship
• International Connection: Australia
• Host: Dr. Laura Mackay