Abstract
Occupational crystalline silica (CS) particle exposure leads to silicosis. The burden of CS-associated disease remains high, and treatment options are limited due to vague mechanisms. Here we show that pulmonary CD4(+) tissue-resident memory T cells (T(RM)) accumulate in response to CS particles, mediating the pathogenesis of silicosis. The T(RM) cells are derived from peripheral lymphocyte recruitment and in situ expansion. Specifically, CD69(+)CD103(+) T(RM)-Tregs depend more on circulating T cell replenishment. CD69 and CD103 can divide the T(RM) cells into functionally distinct subsets, mirroring the immuno-balance within CD4(+) T(RM) cells. However, targeting CD103(+) T(RM)-Tregs do not mitigate disease phenotype since the T(RM) subsets exert immunosuppressive but not pro-fibrotic roles. After identifying pathogenic CD69(+)CD103(-) subsets, we highlight IL-7 for their maintenance and function, that present a promising avenue for mitigating silicosis. Together, our findings highlight the distinct role of CD4(+) T(RM) cells in mediating CS-induced fibrosis and provide potential therapeutic strategies.