Mycobacterium tuberculosis multidrug-resistant strains from Argentina M and Ra enhance IL-17+INFg- cells via TGF-b and IL-23 in MDR-TB

BASILE JUAN; GEFFNER LAURA; RITACCO VIVIANA; VESCOVO MARISA; GARCÍA ANA; CUFFRÉ M; GONZALEZ MONTANER PABLO; SASIAIN MARÍA DEL CARMEM; DE LA BARRERA SILVIA

Vancouver

Simposio; Tuberculosis: Immunology, Cell Biology and Novel Vaccination Strategies (J3); 2011

Keystone Symposia Organization

We have previously demonstrated that INFg positive and IL17 positiveT cells are differentially induced by M and Ra strains in MDRTB patients and healthy individuals, N. IL17 is a heterogeneous population that comprises IL-17+IFNgneg and IL17posIFNgpos 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 from 6 N and 15 MDRTB patients were cultured with and without M, Ra or H37Rv strains for 48 hr in the presence or absence of neutralizing MoAbs against IL23, IL1b, IL6 and TGFb. IL17 and INFg expression was evaluated by flow cytometry and results are expressed as percentage of IL17posINFneg, IL17posIFNpos and IL17negIFNpos cells within the CD4 subset.Results: a) All strains enhanced percentage of IL-17posIFNneg cells in MDRTB and N. M and Ra markedly enhanced the percentage of IL17posIFNneg, being M the highest inducer. Higher percentage IL17posIFNneg was observed in MDRTB compared to N while the percentage IL17posIFNneg was similar in both groups. B) antiIL23, antiIL1b and antiIL6 diminished the percentage of both Th17 subsets in MDRTB and N. In MDRTB, antiTGFb diminished the percentage of IL17posIFNneg and enhanced the percentage of IL17posIFNpos induced by M and Ra while no differences were observed in N. C) the percentage of IL17negINFpos cells in Mtb-stimulated CD4 T cells was lower in MDRTB than in N and neutralization of IL23 and TGFb increased the percentage of IL17negINFpos only in MDRTB patients. Conclusions: IL-17posINFneg cells were the main cells involved in M and Ra induced Th17 response in MDRTB patients being their expansion promoted by TGFb. However, neutralization of TGFb results in an enhancement of IL17posIFNpos and of single INFgpos cells suggesting that Th17 subsets are plastic to cytokine environment. Interestingly, IL23 also inhibited the differentiation of Mtb specific single INFgamma positive cells contributing to the impairment of Th1 response observed in MDRTB patients.