Signaling proteins: regulators of the immune response in tuberculosis

VERÓNICA GARCÍA

Santa Fe

Conferencia; IV Meeting of the Sociedad Latinoamericana de Tuberculosis y otras Micobacteriosis; 2008

Sociedad Latinoamericana de Tuberculosis y otras Micobacteriosis

Tuberculosis remains an enormous global health problem despite current drug treatment. BCG, the only available vaccine, is of variable efficacy especially in tuberculosis-endemic regions.  Development of a more effective vaccine depends on a better understanding of the human immune response to this pathogen.  Resistance to mycobacterial infections is primarily mediated by the interaction of antigen-specific T cells and macrophages.  This interaction is often dependent on the interplay of cytokine produced by these cells.  Therefore, it is considered of vast interest to investigate the regulation of cytokine responses during active tuberculosis.  In fact, the degree of reduction in IFN-g production by peripheral blood mononuclear cells is a marker of disease severity in tuberculosis patients.  Thus, elucidation of the mechanisms for reduced IFN-ã production in individuals that develop the disease will enhance our knowledge of the pathogenesis of tuberculosis.  To understand these mechanisms, it is important to delineate how Th precursor cells activate the IFN-ã gene and become committed to the Th1 phenotype.  Several signaling proteins contribute to the active up- or down-regulation during the priming of a T cell, modulating the pattern of cytokines produced by T cells upon antigen-stimulation.  Accordingly, we demonstrated that SLAM and ICOS enhanced IFN-ã secretion, whereas SAP, CD31 and PD-1 interfered with Th1 responses in tuberculosis.  Moreover, we provided new information linking SLAM to the transcription factor CREB and the proinflammatory cytokine IL-17.  IL-17 inhibited IFN-ã production during tuberculosis, by decreasing the expression/function of stimulatory signaling proteins.  Furthermore,Th17 cells were significantly increased in tuberculosis patients compared to healthy donors.  Thus, increased IL-17 production may regulate the capacity of T cells from tuberculosis patients to produce IFN-ã against mycobacterial antigens.  Additional work is needed to elucidate the pathways that participate in the control of IFN-ã secretion in tuberculosis.