Transforming growth factor-, Interleukin-23 and interleukin-1 modulate TH22 response during active multidrug-resistant tuberculosis

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-1 beta and IL-23 promote Mtb-induced IL-22 secretion and expansion of IL-22(+) cells, TGF-beta inhibits this response. Systemic and in vitro Mtb-induced Th22 response inversely correlates with TGF-beta amounts in plasma and in PBMC cultures respectively. The number of circulating PD-1(+) T cells directly correlates with plasmatic TGF-beta levels and blockade of PD-1/PD-L1 signalling enhances in vitro Mtb-induced expansion of IL-22(+) cells. Thus, TGF-beta 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-1 beta(+) 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-beta secretion than patients with UCC. Thus, high TGF-beta secretion and subtle differences in IL-23 and IL-1 beta expression could diminish systemic and in vitro Mtb-induced Th22 response along disease progression in TB patients.