Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets

Michael E B FitzPatrick; Nicholas M Provine; Lucy C Garner; Kate Powell; Ali Amini; Sophie L Irwin; Helen Ferry; Tim Ambrose; Peter Friend; Georgios Vrakas; Srikanth Reddy; Elizabeth Soilleux; Paul Klenerman; Philip J Allan

doi:10.1016/j.celrep.2020.108661

Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets

Cell Rep. 2021 Jan 19;34(3):108661. doi: 10.1016/j.celrep.2020.108661.

Authors

Affiliations

¹ Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
² Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK.
³ Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK; Oxford Transplant Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK.
⁴ Oxford Transplant Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK.
⁵ Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
⁶ Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK; NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK. Electronic address: paul.klenerman@medawar.ox.ac.uk.
⁷ Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; Oxford Transplant Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK; NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK.

Abstract

Tissue-resident memory T (T_RM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However, transcriptional heterogeneity of human intestinal T_RM cells remains undefined. Here, we investigate transcriptional and functional heterogeneity of human T_RM cells through study of donor-derived T_RM cells from intestinal transplant recipients. Single-cell transcriptional profiling identifies two transcriptional states of CD8⁺ T_RM cells, delineated by ITGAE and ITGB2 expression. We define a transcriptional signature discriminating these populations, including differential expression of cytotoxicity- and residency-associated genes. Flow cytometry of recipient-derived cells infiltrating the graft, and lymphocytes from healthy gut, confirm these CD8⁺ T_RM phenotypes. CD8⁺ CD69⁺CD103⁺ T_RM cells produce interleukin-2 (IL-2) and demonstrate greater polyfunctional cytokine production, whereas β2-integrin⁺CD69⁺CD103^- T_RM cells have higher granzyme expression. Analysis of intestinal CD4⁺ T cells identifies several parallels, including a β2-integrin⁺ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4⁺ and CD8⁺ T_RM cells.

Keywords: CD103; T cell; Tissue resident; human; intestinal transplantation; intestine; residency; transplant; β2-integrin.

Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets

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