Abstract
Background: 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. CD4+ tissue-resident memory T cells (TRM) accumulate in the lung responded to CS particles, mediating the pathogenesis of silicosis.
Methods: Based on silicosis murine model by single intratracheal instillation of CS suspension, we further employ adoptive transfer, FTY720 treatment, and parabiosis murine model to explore their source. After defining TRM cell subsets by CD103 and CD69, we intervene CD103+subset and block IL-7 signaling to alleviate silicosis.
Results: The CD4+ TRM cells are derived from peripheral lymphocyte recruitment and in situexpansion. Specifically, TRM-Treg cells depend more on circulating T cell replenishment. The cell retention markers CD103 and CD69 can divide the TRM cells into effector and regulatory subsets. However, targeting CD103+TRM-Treg cells do not mitigate disease phenotype since the TRM subsets exerted immunosuppressive but not pro-fibrotic roles. We further dissect that IL-7 signaling promotes the progression of silicosis by tuning the maintenance of TRM-effector T cells.
Conclusion: Our findings highlight the distinct role of CD4+ TRM cells in mediating CS-induced fibrosis and provide potential therapeutic strategies for silicosis.
Keywords: crystalline silica; fibrosis; inflammation; silicosis; tissue-resident memory T cells