Control of memory and effector T cell differentiation & maintenance by the mitochondrial protein TCAIM
Cell Biology
Final Report Abstract
To cope with increased metabolic demands arising during activation and differentiation into tissue homing effectors cells, T cells need to upregulate catabolic and to induce anabolic processes. The molecular mechanisms controlling this adaptation are incompletely understood. Previously we could show that expression of the mitochondrial protein T cell activation inhibitor, mitochondrial (TCAIM) is downregulated upon T cell activation. Reinforced TCAIM expression inhibited effector T cell differentiation of conventional CD4+ T cells. TCAIM exclusively locates within mitochondria where it seems to interfere with activation-induced changes in mitochondrial morphology and function. Thereby TCAIM respective its down regulation provides a link between T cell receptor signals, mitochondrial dynamics and effector T cell differentiation. Based on our previous findings we hypothesized TCAIM could act as an important negative regulator of activation-induced mitochondrial alterations and changes in cellular metabolism driving differentiation of tissue homing effector T cells as well as formation and maintenance of tissue resident memory T cells. In the project we discovered that the mitochondrial protein TCAIM plays a pivotal role for mitochondrial signaling and metabolic adaptations. A TCAIM knock-in (KI) impaired the induction of anabolic pathways, especially cholesterol biosynthesis by CD8+ T cells. Although TCAIM KI CD8+ T cells can respond to influenza infections, they fail to differentiate into CD44+/ GZMB+ effector cells able to migrate to the infected lungs. This prevented T cell induced lung pathology but also impaired viral clearance and recovery. Molecularly, TCAIM delayed activation-induced mitochondria-ER contact formation by binding to VDAC2 and RMD3 and by facilitating tubulin-mediated VDAC closure. Consequently, TCAIM KI CD8+ T cells showed reduced stimulation induced mTOR signaling, cholesterol biosynthesis and HIF1α expression. Inhibition of tubulin-mediated VDAC closure by erastin or addition of cholesterol reversed the TCAIM KI CD8+ T cell phenotype. Conclusively, TCAIM acts as a negative regulator of the mitochondrial immunometabolic hub controlling formation of peripheral tissue homing effector and thus tissue resident memory T cells.
Publications
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11th Autumn School Current Concepts in Immunology 2019 The role of the mitochondrial protein TCAIM in the differentiation and maintenance of memory T cells
Kufka, Julia & Sawitzki, Birgit
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19th Annual Meeting FOCIS 2019 The role of the mitochondrial protein TCAIM in controlling CD8+ T cell functions
Iwert, Christina & Sawitzki, Birgit
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DGfI T-Cell Meeting 2019 TCAIM-induced mitochondrial cristae formation inhibits metabolic reprogramming and CD8+ T cell effector differentiation
Iwert, Christina & Sawitzki, Birgit
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II Joint Meeting of the DGfI & SIICA 2019 TCAIM-induced mitochondrial cristae formation inhibits metabolic reprogramming and CD8+ T cell effector differentiation
Iwert, Christina & Sawitzki, Birgit
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Immunmetabolismus –zentraler Kontrollpunkt der T-Zelldifferenzierung und -funktion. Trillium Immunologie 2019; 3(2)
Sawitzki, Birgit & Iwert, Christina
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TCAIM controls effector T cell generation by preventing Mitochondria-Endoplasmic Reticulum Contact Site-initiated Cholesterol Biosynthesis. Cold Spring Harbor Laboratory.
Iwert, Christina; Stein, Julia; Appelt, Christine; Vogt, Katrin; Rainer, Roman Josef; Tummler, Katja; Mühle, Kerstin; Stanko, Katarina; Schumann, Julia; Uebe, Doreen; Jürchott, Karsten; Lisec, Jan; Janek, Katharina; Gille, Christoph; Textoris-Taube, Kathrin; Sai, Somesh; Petersen, Ansgar; Kühl, Anja A.; Klipp, Edda ... & Sawitzki, Birgit
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Cell Symposia: Metabolites in Signaling and Disease (CMET) 2022 Tcaim-mediated inhibition of cholesterol synthesis hampers formation and persistence of influenza-reactive memory T cells
Stein, Julia & Sawitzki, Birgit
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Cell Symposia: Metabolites in Signaling and Disease (CMET) 2022 The mitochondrial protein TCAIM inhibits metabolic reprogramming and effector T cell differentiation through regulation of VDAC2
Iwert, Christina & Sawitzki, Birgit
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Complement activation induces excessive T cell cytotoxicity in severe COVID-19. Cell, 185(3), 493-512.e25.
Georg, Philipp; Astaburuaga-García, Rosario; Bonaguro, Lorenzo; Brumhard, Sophia; Michalick, Laura; Lippert, Lena J.; Kostevc, Tomislav; Gäbel, Christiane; Schneider, Maria; Streitz, Mathias; Demichev, Vadim; Gemünd, Ioanna; Barone, Matthias; Tober-Lau, Pinkus; Helbig, Elisa T.; Hillus, David; Petrov, Lev; Stein, Julia; Dey, Hannah-Philine ... & Sawitzki, Birgit
