Semaphorin 7a⁺ regulatory T cells are associated with progressive idiopathic pulmonary fibrosis and are implicated in transforming growth factor-β1-induced pulmonary fibrosis

Rationale: Lymphocytes are increasingly associated with idiopathic pulmonary fibrosis (IPF). Semaphorin 7a (Sema 7a) participates in lymphocyte activation. Objectives: To define the relationship between Sema 7a and lymphocytes in IPF. Methods: We characterized the significance of Sema 7a ⁺ lymphocytes in humans with IPF and in a mouse model of lung fibrosis caused by lung-targeted, transgenic overexpression of TGF-β1. We determined the site of Sema 7a expression in human and murine lungs and circulation and used adoptive transfer approaches to define the relevance of lymphocytes coexpressing Sema7a and the markers CD19, CD4, or CD4 ⁺CD25⁺FoxP3⁺ in TGF-β1-induced murine lung fibrosis. Measurements and Main Results: Subjects with IPF show expression of Sema 7a on lung CD4⁺ cells and circulating CD4⁺ or CD19⁺ cells. Sema 7a expression is increased on CD4⁺ cells and CD4⁺CD25⁺ FoxP3⁺ regulatory T cells, but not CD19⁺ cells, in subjects with progressive IPF. Sema 7a is expressed on lymphocytes expressing CD4 but not CD19 in the lungs and spleen of TGF-β1-transgenic mice. Sema 7a expressing bone marrow-derived cells induce lung fibrosis and alter the production of T-cell mediators, including IFN-γ, IL-4, IL- 17A, and IL-10. These effects require CD4 but not CD19. In comparison to Sema 7a-CD4⁺CD25⁺FoxP3⁺ cells, Sema7a⁺CD4⁺CD25⁺ FoxP3⁺ cells exhibit reduced expression of regulatory genes such as IL-10, and adoptive transfer of these cells induces fibrosis and remodeling in the TGF-β1-exposed murine lung. Conclusions: Sema 7a⁺CD4 ⁺CD25⁺FoxP3⁺ regulatory T cells are associated with disease progression in subjects with IPF and induce fibrosis in the TGF-β1-exposed murine lung.