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Summary: The role of interleukin‐22 (IL‐22) in the pathogenesis or tissue repair in human tuberculosis (TB) remains to be established. Here, we aimed to explore the ex‐vivo and in‐vitro T helper 22 (Th22) response in TB patients and healthy donors (HD) induced by different local multi‐drug‐resistant (MDR) Mvcobacterium tuberculosis (Mtb) strains. For this purpose, peripheral blood mononuclear cells from drug‐susceptible (S‐TB) MDR‐TB patients and HD were stimulated with local MDR strains and the laboratory strain H37Rv. IL‐22 and IL‐17 expression and senescent status were assessed in CD4+ and CD8+ cells by flow cytometry, while IL‐22 amount was measured in plasma and culture supernatants by enzyme‐linked immunosorbent assay (ELISA). We found lower IL‐22 amounts in plasma from TB patients than HD, together with a decrease in the number of circulating T cells expressing IL‐22. In a similar manner, all Mtb strains enhanced IL‐22 secretion and expanded IL‐22+ cells within CD4+ and CD8+ subsets, being the highest levels detected in S‐TB patients. In MDR‐TB, low systemic and Mtb‐induced Th22 responses associated with high sputum bacillary load and bilateralism of lung lesions, suggesting that Th22 response could be influencing the ability of MDR‐TB patients to control bacillary growth and tissue damage. In addition, in MDR‐TB patients we observed that the higher the percentage of IL‐22+ cells, the lower the proportion of programmed cell death 1 (PD‐1)+ or CD57+ T cells. Furthermore, the highest proportion of senescent T cells was associated with severe lung lesions and bacillary load. Thus, T cell senescence would markedly influence Th22 response mounted by MDR‐TB patients. [ABSTRACT FROM AUTHOR]