Control of memory and effector T cell differentiation & maintenance by the mitochondrial protein TCAIM

• Applicant: Professorin Dr. Birgit Sawitzki
• Subject Area: Immunology ; Cell Biology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 397744835

Our preliminary data revealed that signals received via the T cell receptor or common gamma chain baring cytokine receptors (e.g. IL-2) result in a down-regulation of tcaim expression in CD4+ and CD8+ T cells. TCAIM prevents mitochondrial fission and redistribution upon T cell receptor stimulation but also transcriptional programming towards peripheral tissue homing effector and memory T cells. Thereby TCAIM respective its down-regulation provides a link between T cell receptor signals, mitochondrial dynamics and T cell differentiation. We thus hypothesize, that by inhibiting mitochondrial fission and redistribution TCAIM prevents the metabolic shift from mainly oxidative phosphorylation in naïve T cells towards glycolysis upon T cell activation. This is critical for the differentiation of tissue-homing effector T cells and maintenance of tissue-resident memory T cells. Thus we will study whether: 1) and how TCAIM controls activation of mitochondrial fusion or fission regulating proteins and thus cellular metabolism in T cells,2) TCAIM prevents asymmetric distribution of mitochondria during cell division thereby modulating T cell activation and inhibiting effector T cell differentiation and tissue homing.3) induction of tcaim expression interferes with the maintenance of tissue-resident memory T cells and whether this can be used to mobilize and re-differentiate effector and tissue-resident memory T cells into circulating less inflammatory memory T cells.To answer these questions, we will make use of existing constitutive and inducible (CD4-CreERT2/UBC-CreERT2) T cell-specific Tcaim tg/k.o. mice. The first two aims will be addressed with in vitro experiments applying molecular biology, metabolomics and imaging technologies. To investigate whether TCAIM interferes with the maintenance of tissue-resident memory T cells we will utilize the influenza infection model and study the number, phenotype and function of virus-specific CD4+/CD8+ T cells upon primary and secondary influenza challenge.

• DFG Programme: Research Grants