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

Loss of T cell tolerance in the skin following immunopathology is linked to failed restoration of the dermal niche by recruited macrophages
Loss of T cell tolerance in the skin following immunopathology is linked to failed restoration of the dermal niche by recruited macrophages
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.
CP: immunology, contact hypersensitivity, dermis, disease niche, graft-versus-host disease, macrophages, monocytes, regulatory T cells, skin, tolerance
2211-1247
West, Heather
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Davies, James
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Henderson, Stephen
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Adegun, Oluyori
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Ward, Sophie
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Ferrer, Ivana
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Tye, Chanidapa
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Vallejo Pulido, Andres
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Jardine, Laura
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Colin, Matthew
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Polak, Marta
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Bennett, Clare
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West, Heather
2867f2be-13cc-4651-bfb9-14e587b89a49
Davies, James
0b5e86c3-c2d8-41ca-a94a-a8d5190b0d53
Henderson, Stephen
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Adegun, Oluyori
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Ward, Sophie
8c6557eb-e06d-4110-b186-142accf32cdc
Ferrer, Ivana
83ca59d7-0714-4688-9bc5-b8a6ac866a68
Tye, Chanidapa
ac03c099-ad05-4c40-9af1-c8a69ed6442b
Vallejo Pulido, Andres
27bc0b94-0c40-4fd1-9533-7e267d588c0a
Jardine, Laura
a7a441ca-39e8-423d-9247-44e5888dc621
Colin, Matthew
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Polak, Marta
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Bennett, Clare
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West, Heather, Davies, James, Henderson, Stephen, Adegun, Oluyori, Ward, Sophie, Ferrer, Ivana, Tye, Chanidapa, Vallejo Pulido, Andres, Jardine, Laura, Colin, Matthew, Polak, Marta and Bennett, Clare (2022) Loss of T cell tolerance in the skin following immunopathology is linked to failed restoration of the dermal niche by recruited macrophages. Cell Reports, 39 (7), [110819]. (doi:10.1016/j.celrep.2022.110819).

Record type: Article

Abstract

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.

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Accepted/In Press date: 22 April 2022
Published date: 17 May 2022
Additional Information: Funding Information: We thank the UCL Comparative Biology Unit for their support with animal work, and UCL Genomics for performing the RNA sequencing. We also acknowledge the support of the Cancer Institute Translational Technology Platforms, in particular Elena Miranda in the pathology service, and the flow cytometry core facility. We are grateful to Anne Pesenacker and Victoria Male for their critical and constructive reading of the manuscript. This work was funded by a BBSRC project grant ( BB/L001608/1 ) and Royal Free charity funding (award 174418 ) to C.L.B., as well as an MRC PhD studentship ( 1450227 ) to H.C.W. L.J. and M.C. acknowledge support from a Wellcome Trust Clinical Research Training Fellowship WT097941 and additional funding from the Bright Red charity and M.E.P. is supported by a Sir Henry Dale Fellowship from Wellcome Trust , 109377/Z/15/Z . The graphical abstract was created with BioRender.com . Funding Information: We thank the UCL Comparative Biology Unit for their support with animal work, and UCL Genomics for performing the RNA sequencing. We also acknowledge the support of the Cancer Institute Translational Technology Platforms, in particular Elena Miranda in the pathology service, and the flow cytometry core facility. We are grateful to Anne Pesenacker and Victoria Male for their critical and constructive reading of the manuscript. This work was funded by a BBSRC project grant (BB/L001608/1) and Royal Free charity funding (award 174418) to C.L.B. as well as an MRC PhD studentship (1450227) to H.C.W. L.J. and M.C. acknowledge support from a Wellcome Trust Clinical Research Training Fellowship WT097941 and additional funding from the Bright Red charity and M.E.P. is supported by a Sir Henry Dale Fellowship from Wellcome Trust, 109377/Z/15/Z. The graphical abstract was created with BioRender.com. H.C.W. designed and performed the majority of the experiments, analyzed and interpreted the data. J.D. performed the bulk of the transcriptomics analyses and some experiments, interpreted the data, and helped prepare figures. S.H. provided analysis of the comparison of dermal and epidermal monocyte populations for Figure 1 and the associated supplemental data. O.K.A. scored histology slides. S.W. I.R.F. and C.A.T. performed the experiments and were involved in establishing the models used. A.F.V. and M.E.P. provided technical advice for the analysis of the single-cell dataset, and M.E.P. discussed and critiqued the manuscript. L.J. and M.C. provided human NanoString data. C.L.B. conceived and designed experiments, analyzed and interpreted the data, wrote the manuscript, and supervised the project. All authors contributed to reviewing and editing the manuscript. The authors declare no competing interests. Publisher Copyright: © 2022 The Authors
Keywords: CP: immunology, contact hypersensitivity, dermis, disease niche, graft-versus-host disease, macrophages, monocytes, regulatory T cells, skin, tolerance

Identifiers

Local EPrints ID: 467296
URI: http://eprints.soton.ac.uk/id/eprint/467296
ISSN: 2211-1247
PURE UUID: 9be0a3c1-5700-416d-9cd8-c7e8bbcf9b7b
ORCID for Andres Vallejo Pulido: ORCID iD orcid.org/0000-0002-4688-0598

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Date deposited: 05 Jul 2022 16:49
Last modified: 17 Mar 2024 03:46

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Contributors

Author: Heather West
Author: James Davies
Author: Stephen Henderson
Author: Oluyori Adegun
Author: Sophie Ward
Author: Ivana Ferrer
Author: Chanidapa Tye
Author: Andres Vallejo Pulido ORCID iD
Author: Laura Jardine
Author: Matthew Colin
Author: Marta Polak
Author: Clare Bennett

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