Local Muñiz strain of Mycobacterium tuberculosis induces differential T cell responses in MDR-TB patients

GEFFNER L; YOKOBORI N; BALBOA L; SCHIERLOH P; BASILE J; ROMERO M; ALEMÁN M; RITACCO V; GARCÍA A; VESCOVO M; CUFRÉ M; GONZALEZ MONTANER P; ABBATE E; SASIAIN MC; DE LA BARRERA SS

Keystone, Colorado. USA

Congreso; International symposium of Tuberculosis. “Tuberculosis: Biology, Pathology and Therapy”; 2009

Keystone Symposia TM

In Argentina multidrug-resistant tuberculosis (MOR- TB) outbreaks emerged among hospitalized patients with AlDS in !he ear1y 90´s and disseminated to the community. Several MDR strains responsible for clustered MDR-TB cases have been isolated, including Muñiz strain belonging to Haar1em family (M) which has high infectivity/virulence. It is known that different Mycobacterium tuberculosis (Mtb) strains operate different immune evasion strategies for their survival in the host which mainly depends on me virulence of the strain and the host immune responses. Thus, the aim of this work was to evaluate the cytokine profile and cytotoxic T Iymphocyte (CTL) activity induced by M strain. Methods: PBMC were isolated from MOR-TB patients and PPO+ healthy volunteers (N). Cells were cultured for 5 days alone (C) or wi!h heat-killed H37Rv (Rv) Mtb reference strain or M. Intracellular expression of IL-10, IL-4, IFN-y and surface acquisition of CD107 were determined in C04 and CD8 T cells by flow cytometry. Results: PBMC stimulation with Rv and M enhanced IL-10+ and IFN-y+ expression on C04+ and CD8+ T cells from MDR-TB and N (p<0.05). MDR-TB showed lower %IFN-y+CD4+ and IFN-y+CD8+ T cells than N in response to Rv and M (p<0.05). In MDR-TB, M and Rv increased %IL-4+ in CD4+ and CD8+ (p<0.05) being these levels higher than in N. Furthermore, M- was higher than Rv-induced IL-4 in MDRTB (p<0.05). C0107 up regulation in CD8+ T cells was observed in MDR-TB and N in response to Rv and M. However, CD107+ expression was mainly restricted to CD8+y6+ T cells in MOR-TB and to CD8+y6- in N, suggesting a differential in vitro CTL generation between MDR-TB and N. Interestingly, M did not induce %CD107+CD8+ T cells as Rv did, either in MDR-TB or N (p<0.05) being this fact confirmed by standard 51Cr-release assays (p<0.01). Discussion: MDR-TB per se exhibit low IFN-y and high IL-4 expression in T cells and a CTL mediated by C08+y6+ T cells. In addition, M strain induces even higher Th2 response in MDR-TB. Furthermore, M strain is characterized by a lack of CTL activity even in healthy controls. Our results suggest that interplay between the virulence of the strain and the host immune response is taking place in MDR-TB resulting in M strain persistence in our community. This work was supported by PIP 6170 (CONICET) and PICT 05- 38196 (ANPCyT).