RESUMEN
T cell production of IFN-gamma contributes to host defense against infection by intracellular pathogens, including mycobacteria. Lepromatous leprosy, the disseminated form of infection caused by Mycobacterium leprae, is characterized by loss of cellular response against the pathogen and diminished Th1 cytokine production. Relieving bacterial burden in Ag-unresponsive patients might be achieved through alternative receptors that stimulate IFN-gamma production. We have previously shown that ligation of signaling lymphocytic activation molecule (SLAM) enhances IFN-gamma in mycobacterial infection; therefore, we investigated molecular pathways leading from SLAM activation to IFN-gamma production in human leprosy. The expression of the SLAM-associated protein (an inhibitory factor for IFN-gamma induction) on M. leprae-stimulated cells from leprosy patients was inversely correlated to IFN-gamma production. However, SLAM ligation or exposure of cells from lepromatous patients to a proinflammatory microenvironment down-regulated SLAM-associated protein expression. Moreover, SLAM activation induced a sequence of signaling proteins, including activation of the NF-kappaB complex, phosphorylation of Stat1, and induction of T-bet expression, resulting in the promotion of IFN-gamma production, a pathway that remains quiescent in response to Ag in lepromatous patients. Therefore, our findings reveal a cascade of molecular events during signaling through SLAM in leprosy that cooperate to induce IFN-gamma production and strongly suggest that SLAM might be a focal point for therapeutic modulation of T cell cytokine responses in diseases characterized by dysfunctional Th2 responses.
Asunto(s)
Adyuvantes Inmunológicos/fisiología , Glicoproteínas/fisiología , Inmunoglobulinas/fisiología , Líquido Intracelular/inmunología , Líquido Intracelular/microbiología , Péptidos y Proteínas de Señalización Intracelular , Mycobacterium leprae/inmunología , Transducción de Señal/inmunología , Células TH1/inmunología , Células TH1/metabolismo , Adyuvantes Inmunológicos/metabolismo , Antígenos CD , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/biosíntesis , Células Cultivadas , Citocinas/fisiología , Proteínas de Unión al ADN/metabolismo , Regulación hacia Abajo/inmunología , Glicoproteínas/inmunología , Glicoproteínas/metabolismo , Humanos , Inmunoglobulinas/inmunología , Inmunoglobulinas/metabolismo , Líquido Intracelular/enzimología , Líquido Intracelular/metabolismo , Lepra/enzimología , Lepra/inmunología , Lepra/metabolismo , Ligandos , Activación de Linfocitos/inmunología , FN-kappa B/metabolismo , Transporte de Proteínas/inmunología , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-fyn , Receptores de Superficie Celular , Factor de Transcripción STAT1 , Índice de Severidad de la Enfermedad , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Proteínas de Dominio T Box , Células TH1/enzimología , Células TH1/microbiología , Transactivadores/metabolismo , Factores de Transcripción/biosíntesisRESUMEN
Phagocytic immune cells (particularly macrophages and neutrophils) take up and digest particles that have invaded our bodies. In doing so, they represent a very early line of defence against a microbial attack. During uptake, the particles are wrapped by a portion of the phagocyte's plasma membrane, and a new endocytic compartment, the phagosome, is formed. The typical fate of a phagosome is its fusion with lysosomes to yield a phagolysosome in which the particle is digested. Recent data show that some 'intracellular microorganisms' that can cause severe illnesses (tuberculosis, leprosy, legionnaire's disease and others) manage to reprogramme the host phagocytes not to deliver them to the lysosomal compartment. This probably results in increased survival of the pathogens. The analysis of the composition of such 'novel' compartments and research on the molecular mechanisms underlying the microbial interference with host cell functions are likely to yield important insights into: (1) which endocytic/phagocytic compartments phagocytes employ to handle ingested material in general; (2) how some pathogenic microorganisms can reprogramme the phagocytic pathway; and possibly (3) how infections caused by these microorganisms can be treated more effectively. Here, some studies are presented analysing which compartments intracellular pathogens inhabit and how microbes might be able to reprogramme their host cells.