Activation of Signaling Lymphocytic Activation Molecule Triggers a Signaling Cascade That Enhances Th1 Responses in Human Intracellular Infection

摘要

T cell production of IFN-γ 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-γ production. We have previously shown that ligation of signaling lymphocytic activation molecule (SLAM) enhances IFN-γ in mycobacterial infection; therefore, we investigated molecular pathways leading from SLAM activation to IFN-γ production in human leprosy. The expression of the SLAM-associated protein (an inhibitory factor for IFN-γ induction) on M. leprae -stimulated cells from leprosy patients was inversely correlated to IFN-γ 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-κB complex, phosphorylation of Stat1, and induction of T-bet expression, resulting in the promotion of IFN-γ 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-γ 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.