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Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. The let-7 family of miRNAs is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the let-7 family is downregulated in patients with COPD, however, how they cause emphysema remains unclear. Here we show that overall expression of the let-7 miRNA clusters, let-7b/let-7c2 and let-7a1/let 7f1/let-7d, are reduced in the lungs and T cells of smokers with emphysema as well as in mice with cigarette smoke (CS)-or nCB-elicited emphysema. We demonstrate that loss of the let-7b/let 7c2-cluster in T cells predisposed mice to exaggerated CS-or nCB-elicited emphysema. Furthermore, ablation of the let-7b/let-7c2-cluster enhanced CD8+ IL17a+ T cells (Tc17 …