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We previously reported that patients with multidrug‐resistant tuberculosis (MDR‐TB) showed low systemic and Mtb‐induced Th22 responses associated to high sputum bacillary load and severe lung lesions suggesting that Th22 response could influence the ability of these patients to control bacillary growth and tissue damage. In MDR‐TB patients, the percentage of IL‐22+ cells inversely correlates with the proportion of senescent PD‐1+ T cells. Herein, we aimed to evaluate the pathways involved on the regulation of systemic and Mtb‐induced Th22 response in MDR‐TB and fully drug‐susceptible TB patients (S‐TB) and healthy donors. Our results show that while IL‐1β and IL‐23 promote Mtb‐induced IL‐22 secretion and expansion of IL‐22+ cells, TGF‐β inhibits this response. Systemic and in vitro Mtb‐induced Th22 response inversely correlates with TGF‐β amounts in plasma and in PBMC cultures respectively. The number of circulating PD‐1+ T cells directly correlates with plasmatic TGF‐β levels and blockade of PD‐1/PD‐L1 signalling enhances in vitro Mtb‐induced expansion of IL‐22+ cells. Thus, TGF‐β could also inhibit Th22 response through upregulation of PD‐1 expression in T cells. Higher percentage of IL‐23+ monocytes was observed in TB patients. In contrast, the proportion of IL‐1β+ monocytes was lower in TB patients with bilateral lung cavities (BCC) compared to those patients with unilateral cavities (UCC). Interestingly, TB patients with BCC showed higher plasmatic and Mtb‐induced TGF‐β secretion than patients with UCC. Thus, high TGF‐β secretion and subtle differences in IL‐23 and IL‐1β expression could diminish systemic and in vitro Mtb‐induced Th22 response along disease progression in TB patients. [ABSTRACT FROM AUTHOR]