Center for Molecular Medicine Cologne

Corrado, Mauro - B 03

Epigenetic-metabolic crosstalk in the development of T cell immunological memory

Introduction

T cells dynamically expand and contract following antigen-specific stimuli and microenvironmental cues. As a result, immunological memory protects us from following antigen-specific attacks. Alterations of the mechanisms regulating this process are responsible for autoimmunity or impaired immune protection. Mitochondrial fitness centrally regulates memory T cell differentiation and function. It provides metabolic reserve capacity to allow long lasting survival of memory T cells. It also controls critical steps in epigenetic remodeling, chromatin accessibility and transcriptional profile of T cells by producing and buffering Acetyl-CoA and other metabolites. By combining the analysis of gene expression and chromatin accessibility of effector and memory T cells, we identified previously uncharacterized common hits regulated during memory T cell differentiation. Of note, these hits share a signature for some specific transcription factors, whose role in the immune system has never been studied. We hypothesize that these transcription factors might integrate metabolic and epigenetic signals to establish persistent immunological memory. By complementing metabolic and immunologic phenotyping with cutting edge sequencing approaches, the project will reveal novel insights into the epigenetic and metabolic network necessary to establish long-term immune memory and surveillance against cancer and recurrent infections.

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    Clinical Relevance

    Establishing long-term immune memory able to recognize and fight previously encountered antigens is central to the success of any vaccination campaigns or cancer immunotherapy. Nevertheless, the mechanisms underlying induction and maintenance of immunological memory still remain elusive. Our line of research aims at identifying and characterize metabolic and epigenetic checkpoints to be exploited in cancer immunotherapy or to improve current and future vaccine regimens.

    In this regard, metabolism has a central role in memory T cell generation. It is therefore not surprising that patients affected by mitochondrial diseases (MDs) also show immune defects linking systemic metabolism to immune function alteration (Corrado and Pearce, 2022). Up to half of the patients with MDs experience recurrent or severe upper respiratory tract infections, often resulting in life-threatening conditions. This percentage increases to almost 90% of pediatric MD patients. We hypothesize and investigate how mitochondrial and metabolic deficiencies might underlie and explain (at least partially) the high variability in terms of prognosis after an infection or after the diagnosis of an autoimmune disorder.

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    Approach

    • Integrate epigenetic and transcriptional profiles of TEFF and TMEM cells
    • Identify and validate the role of transcription factors regulated during memory T cell differentiation via pharmacological inhibition and genetic deletion in primary T cells
    • Generate a T cell specific KO mouse model of the most promising validated transcription factor
    • Study the immune response to infection and the in vivo mechanism of TMEM cells generation in the KO mouse model
    • Guhathakurta S, Erdogdu NU, Hoffmann JJ, Grzadzielewska I, Schendzielorz A, Seyfferth J, Martensson CU, Corrado M, Karoutas A, Warscheid B, Pfanner N, Becker T, and Akhtar A (2023). COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function. Nat Metab 5, 1931-1952. doi:10.1038/s42255-023-00904-w.
    Dr. Mauro Corrado CMMC Cologne
    Dr. Mauro Corrado

    CECAD Research Center

    CMMC - PI - B 03
    CMMC - PI - CAP 21
    CMMC - Co-PI - B 02

    +49 221 478 84167

    CECAD Research Center

    Joseph-Stelzmann-Str. 26

    50931 Cologne

    CMMC Profile Page

    Curriculum Vitae (CV)

    Publications - Mauro Corrado

    Link to PubMed

    Group Members

    PhD students:
    Regina Annamaria
    Sara Gjurgji
    Master students:
    Irma Alibashikj
    Sivanesan Pujyanathan
    Keanu Haenen
    Yevheniia Minchuk
    Technician:
    Jessica Büchel