Human Liver Memory CD8+ T Cells Use Autophagy for Tissue Residence
Leo Swadling,
Laura J. Pallett,
Mariana O. Diniz,
Josephine M. Baker,
Oliver E. Amin,
Kerstin A. Stegmann,
Alice R. Burton,
Nathalie M. Schmidt,
Anna Jeffery-Smith,
Nekisa Zakeri,
Kornelija Suveizdyte,
Farid Froghi,
Giuseppe Fusai,
William M. Rosenberg,
Brian R. Davidson,
Anna Schurich,
A. Katharina Simon,
Mala K. Maini
Affiliations
Leo Swadling
Division of Infection and Immunity, University College London, London, UK; Corresponding author
Laura J. Pallett
Division of Infection and Immunity, University College London, London, UK
Mariana O. Diniz
Division of Infection and Immunity, University College London, London, UK
Josephine M. Baker
Division of Infection and Immunity, University College London, London, UK
Oliver E. Amin
Division of Infection and Immunity, University College London, London, UK
Kerstin A. Stegmann
Division of Infection and Immunity, University College London, London, UK
Alice R. Burton
Division of Infection and Immunity, University College London, London, UK
Nathalie M. Schmidt
Division of Infection and Immunity, University College London, London, UK
Anna Jeffery-Smith
Division of Infection and Immunity, University College London, London, UK; Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, QMUL, London, UK
Nekisa Zakeri
Division of Infection and Immunity, University College London, London, UK
Kornelija Suveizdyte
Division of Infection and Immunity, University College London, London, UK
Farid Froghi
Institute for Liver and Digestive Health, University College London, London, UK
Giuseppe Fusai
Institute for Liver and Digestive Health, University College London, London, UK
William M. Rosenberg
Institute for Liver and Digestive Health, University College London, London, UK
Brian R. Davidson
Institute for Liver and Digestive Health, University College London, London, UK
Anna Schurich
Division of Infection and Immunity, University College London, London, UK; Department of Infectious Diseases, Kings College London, London, UK
A. Katharina Simon
The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
Mala K. Maini
Division of Infection and Immunity, University College London, London, UK; Corresponding author
Summary: Tissue-resident memory T cells have critical roles in long-term pathogen and tumor immune surveillance in the liver. We investigate the role of autophagy in equipping human memory T cells to acquire tissue residence and maintain functionality in the immunosuppressive liver environment. By performing ex vivo staining of freshly isolated cells from human liver tissue, we find that an increased rate of basal autophagy is a hallmark of intrahepatic lymphocytes, particularly liver-resident CD8+ T cells. CD8+ T cells with increased autophagy are those best able to proliferate and mediate cytotoxicity and cytokine production. Conversely, blocking autophagy induction results in the accumulation of depolarized mitochondria, a feature of exhausted T cells. Primary hepatic stellate cells or the prototypic hepatic cytokine interleukin (IL)-15 induce autophagy in parallel with tissue-homing/retention markers. Inhibition of T cell autophagy abrogates tissue-residence programming. Thus, upregulation of autophagy adapts CD8+ T cells to combat mitochondrial depolarization, optimize functionality, and acquire tissue residence. : Swadling et al. show that an increased rate of basal autophagy is a hallmark of intrahepatic lymphocytes, particularly liver-resident CD8+ T cells and that in vitro TRM programming requires autophagy induction. Upregulation of autophagy adapts CD8+ T cells to combat mitochondrial depolarization, optimize functionality, and acquire tissue residence. Keywords: autophagy, T cell, liver, tissue-resident, hepatitis B virus, mitophagy, IL-15, immunometabolism
