Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus-Like Inflammation

Nazgol-Sadat Haddadi, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, United States.
Purvi Mande, Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United States.
Tia Y. Brodeur, Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United States.
Kaiyuan Hao, Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United States.
Grace E. Ryan, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, United States.
Stephanie Moses, Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United States.
Sharon Subramanian, Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United States.
Xhuliana Picari, Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United States.
Khashayar Afshari, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, United States.
Ann Marshak-Rothstein, Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, United States.
Jillian M. Richmond, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, United States.

Document Type

Article

Publication Title

Frontiers in immunology

Abstract

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 Page

883375

DOI

10.3389/fimmu.2022.883375

Publication Date

1-1-2022

Identifier

35833127 (pubmed); PMC9271959 (pmc); 10.3389/fimmu.2022.883375 (doi)

This document is currently not available here.

Share

COinS