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 Th22 response in TB patients and healthy donors (HD) induced by different local multidrug-resistant (MDR) M. 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 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. All Mtb strains enhanced in a similar manner 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 to 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 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.This article is protected by copyright. All rights reserved.