Loss of T cell tolerance in the skin following immunopathology is linked to failed restoration of the dermal niche by recruited macrophages
Heather C. West,
James Davies,
Stephen Henderson,
Oluyori K. Adegun,
Sophie Ward,
Ivana R. Ferrer,
Chanidapa A. Tye,
Andres F. Vallejo,
Laura Jardine,
Matthew Collin,
Marta E. Polak,
Clare L. Bennett
Affiliations
Heather C. West
Department of Haematology, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Institute for Immunity and Transplantation, Division of Infection and Immunity, University College London, London NW3 2PF, UK
James Davies
Department of Haematology, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Institute for Immunity and Transplantation, Division of Infection and Immunity, University College London, London NW3 2PF, UK
Stephen Henderson
Bill Lyons Informatics Centre, Cancer Institute, University College London, London WC1E 6DD, UK
Oluyori K. Adegun
Department of Cellular Pathology, University College London Hospitals NHS Foundation Trust, London, UK
Sophie Ward
Department of Haematology, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Institute for Immunity and Transplantation, Division of Infection and Immunity, University College London, London NW3 2PF, UK
Ivana R. Ferrer
Department of Haematology, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Institute for Immunity and Transplantation, Division of Infection and Immunity, University College London, London NW3 2PF, UK
Chanidapa A. Tye
Department of Haematology, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Institute for Immunity and Transplantation, Division of Infection and Immunity, University College London, London NW3 2PF, UK
Andres F. Vallejo
Clinical and Experimental Sciences (Sir Henry Wellcome Laboratories, Faculty of Medicine) and Institute for Life Sciences, University of Southampton, Southampton, UK
Laura Jardine
Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
Matthew Collin
Newcastle University Translational and Clinical Research Institute and NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle Upon Tyne, UK
Marta E. Polak
Clinical and Experimental Sciences (Sir Henry Wellcome Laboratories, Faculty of Medicine) and Institute for Life Sciences, University of Southampton, Southampton, UK
Clare L. Bennett
Department of Haematology, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Institute for Immunity and Transplantation, Division of Infection and Immunity, University College London, London NW3 2PF, UK; Corresponding author
Summary: T cell pathology in the skin leads to monocyte influx, but we have little understanding of the fate of recruited cells within the diseased niche, or the long-term impact on cutaneous immune homeostasis. By combining a murine model of acute graft-versus-host disease (aGVHD) with analysis of patient samples, we demonstrate that pathology initiates dermis-specific macrophage differentiation and show that aGVHD-primed macrophages continue to dominate the dermal compartment at the relative expense of quiescent MHCIIint cells. Exposure of the altered dermal niche to topical haptens after disease resolution results in hyper-activation of regulatory T cells (Treg), but local breakdown in tolerance. Disease-imprinted macrophages express increased IL-1β and are predicted to elicit altered TNF superfamily interactions with cutaneous Treg, and we demonstrate the direct loss of T cell regulation within the resolved skin. Thus, T cell pathology leaves an immunological scar in the skin marked by failure to re-set immune homeostasis.
