Multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (Mtb) M and Ra expand IL-17+IFNƒ×- cells via TGF-ƒÒ and IL-23-induced inhibition of IFN-g response in MDR-TB patients.

BASILE, JUAN; ; GEFFNER, LAURA; RITACCO VIVIANA; VESCOVO MARISA; GARCIA, ANA; CUFFRE, MÓNICA;; GONZALEZ MONTANER, P;; SASIAIN, M. DEL CARMEN; ; DE LA BARRERA, SILVIA.

Congreso; Primer Congreso Franco-Argentino de Inmunologia; 2010

We have previously demonstrated that INFg+ and IL-17+ T cells are differentially induced by M and Ra strains in MDR-TB patients and healthy individuals (N). IL-17 is a heterogeneous population that comprises IL-17+IFNg- and IL-17+IFNg+ cells. Thus in the present work we evaluated the contribution of both subsets to the whole Mtb-induced Th17 response and their modulation by Th17 inducing cytokines. Peripheral mononuclear blood cells (PMBC) from 6 N and 15 MDR-TB patients were cultured with and without M, Ra or H37Rv strains for 48 hr in the presence or absence of neutralizing MoAbs against IL-23, IL-1£], IL-6 and TGF-£]. IL-17 and INFg expression was evaluated by flow cytometry and results are expressed as % of IL-17+INFg -, IL-17+IFNg + and IL-17-IFNg+ cells within the CD4 subset. Results: a) All strains enhanced %IL-17+IFNg+cells in MDR-TB and N (p<0.05). M and Ra markedly enhanced the %IL-17+IFNg- (p<0.05), being M the highest inducer (p<0.05). Higher % IL-17+IFNg- was observed in MDR-TB compared to N (p<0.05) while the %IL-17+IFNg+ was similar in both groups. B) a-IL23, a-IL-1£] and a-IL-6 diminished the percentage of both Th17 subsets in MDR-TB and N (p<0.05). In MDR-TB, a-TGF-£] diminished %IL-17+IFNg- and enhanced %IL-17+IFNg+ induced by M and Ra (p<0.05) while no differences were observed in N. C) %IL-17-INFg+ cells in Mtb-stimulated CD4+ T cells was lower in MDR-TB than in N (p<005) and neutralization of IL-23 and TGF-£]  increased the %IL17-INFg+ only in MDR-TB patients (p<0.05). Conclusions: IL-17+INFg- cells were the main cells involved in M and Ra-induced Th17 response in MDR-TB patients being their expansion promoted by TGF-£]. However, neutralization of TGF-£] results in an enhancement of IL-17+IFNg+ and of single INFg+ cells suggesting that Th17 subsets are plastic to cytokine environment. Interestingly, IL-23 also inhibited the differentiation of Mtb-specific single INFg+ cells contributing to the impairment of Th1 response observed in MDR-TB patients.