Loss of T cell tolerance in the skin following immunopathology is linked to failed restoration of the dermal niche by recruited macrophages

• Published in: Cell reports (Cambridge) Vol. 39; no. 7; p. 110819
• Main Authors: West, Heather C., Davies, James, Henderson, Stephen, Adegun, Oluyori K., Ward, Sophie, Ferrer, Ivana R., Tye, Chanidapa A., Vallejo, Andres F., Jardine, Laura, Collin, Matthew, Polak, Marta E., Bennett, Clare L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.05.2022; Cell Press; Elsevier
• Subjects: contact hypersensitivity; CP: immunology; dermis; disease niche; graft-versus-host disease; macrophages; monocytes; regulatory T cells; skin; tolerance; regulatory T cells; monocytes; macrophages; CP: immunology; disease niche; skin; contact hypersensitivity; graft-versus-host disease; tolerance; dermis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110819

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. [Display omitted] •Skin immune pathology drives dermis-specific monocyte differentiation•GVHD-primed macrophages dominate the dermis after disease•T cell tolerance to topical haptens fails despite recovery from GVHD•Tregs are dysfunctional within the altered dermal niche The impact of T cell pathology on cutaneous immunity is not well understood. Here, West et al. combine a model of graft-versus-host-disease with patient data to reveal prolonged dysregulation of dermal macrophage differentiation, and breakdown in Treg function, leading to a failure to re-set the skin immune balance after disease.