Tolerogenic lung allograft microenvironment suppresses pathogenic tissue remodeling following respiratory virus infection in mice.

Tolerance after lung transplantation is associated with the induction of Foxp3⁺ regulatory T cell-enriched bronchus-associated lymphoid tissue, which suppresses local and systemic alloimmune responses. How this tolerogenic graft environment shapes responses to respiratory viral infections, a known contributor to adverse outcomes after lung transplantation, remains unknown. Using a mouse model of a seasonally circulating parainfluenza virus, we found that acute infection of tolerant lung allografts results in temporary reductions of both bronchus-associated lymphoid tissue size and abundance of graft-resident Foxp3⁺ cells but does not trigger rejection. At late time points, pathologic chronic type 2 inflammatory responses characteristic of severe parainfluenza virus infection decreased and Krt5⁺ and Krt8⁺ lesions were reduced in tolerant allografts when compared with infected native lungs or syngeneic grafts. This reduction in dysplastic alveolar regeneration in tolerant allografts was associated with an increase in amphiregulin-expressing Foxp3⁺ cells. Furthermore, type II alveolar epithelial cells in lung allografts upregulated genes related to injury when recipient Foxp3⁺ cells were deficient in amphiregulin. These findings shed new light on how immune pathways that are established in tolerant lung allografts, in addition to preventing rejection, protect against aberrant tissue repair after a clinically relevant respiratory viral infection.