Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus–Like Inflammation
Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease characterized by a strong IFN signature, normally associated with type I IFNs. However, increasing evidence points to an additional role for IFNγ, or at least a pathogenic T effector subset dependent on IFNγ, for disease progression....
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.883375/full |
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| author | Nazgol-Sadat Haddadi Purvi Mande Tia Y. Brodeur Kaiyuan Hao Grace E. Ryan Stephanie Moses Sharon Subramanian Xhuliana Picari Khashayar Afshari Ann Marshak-Rothstein Jillian M. Richmond |
| author_facet | Nazgol-Sadat Haddadi Purvi Mande Tia Y. Brodeur Kaiyuan Hao Grace E. Ryan Stephanie Moses Sharon Subramanian Xhuliana Picari Khashayar Afshari Ann Marshak-Rothstein Jillian M. Richmond |
| author_sort | Nazgol-Sadat Haddadi |
| collection | DOAJ |
| description | Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease characterized by a strong IFN signature, normally associated with type I IFNs. However, increasing evidence points to an additional role for IFNγ, or at least a pathogenic T effector subset dependent on IFNγ, for disease progression. Nevertheless, Th2 effector subsets have also been implicated in CLE. We have now assessed the role of specific T cell subsets in the initiation and persistence of skin disease using a T cell-inducible murine model of CLE, dependent on KJ1-26 T cell recognition of an ovalbumin fusion protein. We found that only Th2-skewed cells, and not Th1-skewed cells, induced the development of skin lesions. However, we provide strong evidence that the Th2 disease-initiating cells convert to a more Th1-like functional phenotype in vivo by the time the skin lesions are apparent. This phenotype is maintained and potentiates over time, as T cells isolated from the skin, following a second induction of self-antigen, expressed more IFN-γ than T cells isolated at the time of the initial response. Transcriptional analysis identified additional changes in the KJ1-26 T cells at four weeks post injection, with higher expression levels of interferon stimulated genes (ISGs) including CXCL9, IRF5, IFIH1, and MX1. Further, injection of IFN-γ-/- T cells faied to induce skin disease in mice. We concluded that Th2 cells trigger skin lesion formation in CLE, and these cells switch to a Th1-like phenotype in the context of a TLR7-driven immune environment that is stable within the T cell memory compartment. |
| first_indexed | 2024-12-12T15:17:48Z |
| format | Article |
| id | doaj.art-32f5e6333f6d49e8a5ab52fd9cd4b573 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T15:17:48Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-32f5e6333f6d49e8a5ab52fd9cd4b5732022-12-22T00:20:27ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-06-011310.3389/fimmu.2022.883375883375Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus–Like InflammationNazgol-Sadat Haddadi0Purvi Mande1Tia Y. Brodeur2Kaiyuan Hao3Grace E. Ryan4Stephanie Moses5Sharon Subramanian6Xhuliana Picari7Khashayar Afshari8Ann Marshak-Rothstein9Jillian M. Richmond10Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, United StatesDepartment of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United StatesDepartment of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United StatesDepartment of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United StatesDepartment of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, United StatesDepartment of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United StatesDepartment of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United StatesDepartment of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United StatesDepartment of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, United StatesDepartment of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United StatesDepartment of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, United StatesCutaneous lupus erythematosus (CLE) is an autoimmune skin disease characterized by a strong IFN signature, normally associated with type I IFNs. However, increasing evidence points to an additional role for IFNγ, or at least a pathogenic T effector subset dependent on IFNγ, for disease progression. Nevertheless, Th2 effector subsets have also been implicated in CLE. We have now assessed the role of specific T cell subsets in the initiation and persistence of skin disease using a T cell-inducible murine model of CLE, dependent on KJ1-26 T cell recognition of an ovalbumin fusion protein. We found that only Th2-skewed cells, and not Th1-skewed cells, induced the development of skin lesions. However, we provide strong evidence that the Th2 disease-initiating cells convert to a more Th1-like functional phenotype in vivo by the time the skin lesions are apparent. This phenotype is maintained and potentiates over time, as T cells isolated from the skin, following a second induction of self-antigen, expressed more IFN-γ than T cells isolated at the time of the initial response. Transcriptional analysis identified additional changes in the KJ1-26 T cells at four weeks post injection, with higher expression levels of interferon stimulated genes (ISGs) including CXCL9, IRF5, IFIH1, and MX1. Further, injection of IFN-γ-/- T cells faied to induce skin disease in mice. We concluded that Th2 cells trigger skin lesion formation in CLE, and these cells switch to a Th1-like phenotype in the context of a TLR7-driven immune environment that is stable within the T cell memory compartment.https://www.frontiersin.org/articles/10.3389/fimmu.2022.883375/fullcutaneous lupus erythematosusCD4+ helper T cellLupus flareCXCR6Th1 & Th2 |
| spellingShingle | Nazgol-Sadat Haddadi Purvi Mande Tia Y. Brodeur Kaiyuan Hao Grace E. Ryan Stephanie Moses Sharon Subramanian Xhuliana Picari Khashayar Afshari Ann Marshak-Rothstein Jillian M. Richmond Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus–Like Inflammation Frontiers in Immunology cutaneous lupus erythematosus CD4+ helper T cell Lupus flare CXCR6 Th1 & Th2 |
| title | Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus–Like Inflammation |
| title_full | Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus–Like Inflammation |
| title_fullStr | Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus–Like Inflammation |
| title_full_unstemmed | Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus–Like Inflammation |
| title_short | Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus–Like Inflammation |
| title_sort | th2 to th1 transition is required for induction of skin lesions in an inducible and recurrent murine model of cutaneous lupus like inflammation |
| topic | cutaneous lupus erythematosus CD4+ helper T cell Lupus flare CXCR6 Th1 & Th2 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.883375/full |
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