IL-17A-Secreting Memory γδ T Cells Play a Pivotal Role in Sensitization and Development of Hypersensitivity Pneumonitis

Abstract

Hypersensitivity pneumonitis (HP) typically presents with interstitial inflammation and granulomas induced by an aberrant immune response to inhaled Ags in sensitized individuals. Although IL-17A is involved in the development of HP, the cellular sources of IL-17A and the mechanisms by which IL-17A contributes to granuloma formation remain unclear. Recent studies report that γδ T cells produce IL-17A and exhibit memory properties in various diseases. Therefore, we focused on IL-17A-secreting memory γδ T cells in the sensitization phase and aimed to elucidate the mechanisms by which IL-17A contributes to granuloma formation in HP. We induced a mouse model of HP using pigeon dropping extract (PDE) in wild-type and IL-17A knockout (IL-17A^-/-) mice. IL-17A^-/- mice exhibited reduced granulomatous areas, attenuated aggregation of CD11b⁺ alveolar macrophages, and reduced levels of CCL2, CCL4, and CCL5 in the bronchoalveolar lavage fluid. Among IL-17A⁺ cells, more γδ T cells than CD4⁺ cells were detected after intranasal PDE administration. Interestingly, the expansion of IL-17A-secreting Vγ4⁺ or Vγ1^-Vγ4^- cells of convalescent mice was enhanced in response to the sensitizing Ag. Additionally, coculture of macrophages with PDE and Vγ4⁺ cells purified from PDE-exposed convalescent mice produced significantly more IL-17A than coculture with Vγ4⁺ cells from naive mice. Our findings demonstrate that in the sensitization phase of HP, IL-17A-secreting memory γδ T cells play a pivotal role. Furthermore, we characterized the IL-17A/CCL2, CCL4, CCL5/CD11b⁺ alveolar macrophage axis, which underlies granuloma formation in HP. These findings may lead to new clinical examinations or therapeutic targets for HP.