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Deciphering epigenetically imprinted functional adaptations of tissue-resident memory T cells to guide improved immunotherapy of solid tumors

Applicant Dr. Thomas Müller
Subject Area Immunology
Term from 2022 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 496946670
 
Final Report Year 2024

Final Report Abstract

This project focused on the 98% of the human body’s T cells that temporarily or permanently reside in tissues. Importantly, tissues provide specific environmental niches, largely different from blood, to which tissue-resident memory T cells are adapting. An important open question has been so far, how T cells are regulated to maintain a fine balance between tissue homeostasis at steady state and potent cytotoxic effector functions in case of an infection. To close this knowledge gap, we isolated T cells from nine different organs across the human body and performed in-depth phenotypic characterization using high-parameter flow cytometry paired with state-of-the-art in vitro mechanistic studies to decipher regulatory mechanisms and functions of key effector molecules. In a nutshell, we observed clear differences in cytotoxic effector molecule expression (particularly Granzyme B and Perforin) between blood- and tissue-derived T cells and could demonstrate that environmental cues present in tissues actively dampen cytotoxic potential at steady state. However, upon removal of these cues and/or potent stimulation, tissue-resident T cells can regain cytotoxic effector potential. This indicates a particularly tight regulation of T cell cytotoxicity in tissues, likely as a mechanism to maintain tissue homeostasis at steady state. Another focus of this project was the study of cellular immunity to the SARS-CoV-2 (SCoV-2) virus, particularly in the context of immunosuppression and the emerging mutational leap variants Omicron BA.1. and Pirola BA.2.86. We studied SCoV-2-reactive T cell responses in large clinical cohorts that comprised healthy individuals as well as five different groups of immunocompromised states. Our main findings include that: (1) booster vaccination has been absolutely key for inducing strong anti-SCoV-2 cellular immunity in individuals that poorly responded to first two vaccine doses; (2) ancestral Wu-Hu.1-based mRNA vaccine-induced T cell responses were able to potently cross-recognize mutational leap variants that largely evaded antibody responses due to the high amount of mutations in the spike protein. Hence, conserved and robust T cell responses might have been an extra layer of protection that prevented excessive death rates during the Omicron and Pirola waves; (3) repeated stimulation through booster vaccination doses was not observed to have detrimental effects on T cell physiology and function; (4) despite strong clonal T cell expansion in response to the ancestral spike protein, we observed formation of Omicron BA.1-mutant spike epitope-specific T cell responses in individuals with hybrid immunity. Hence, our data indicate a certain degree of conserved adaptability of the T cell compartment, rather than so-called antigenic sin effects that have been speculated earlier to prevent induction of SCoV-2 mutant-specific T cells.

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