IL-21 Promotes Pulmonary Fibrosis through the Induction of Profibrotic CD8+ T Cells

Type 2 effector production of IL-13, a demonstrated requirement in models of fibrosis, is routinely ascribed to CD4+ Th2 cells. We now demonstrate a major role for CD8+ T cells in a murine model of sterile lung injury. These pulmonary CD8+ T cells differentiate into IL-13–producing Tc2 cells and play a major role in a bleomycin-induced model of fibrosis. Differentiation of these Tc2 cells in the lung requires IL-21, and bleomycin treated IL-21– and IL-21R–deficient mice develop inflammation but not fibrosis. Moreover, IL-21R–expressing CD8+ cells are sufficient to reconstitute the fibrotic response in IL-21R–deficient mice. We further show that the combination of IL-4 and IL-21 skews naive CD8+ T cells to produce IL-21, which, in turn, acts in an autocrine manner to support robust IL-13 production. Our data reveal a novel pathway involved in the onset and regulation of pulmonary fibrosis and identify Tc2 cells as key mediators of fibrogenesis.