Activation of signaling lymphocytic activation molecule triggers a signaling cascade that enhances Th1 responses in human intracellular infection.
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.
Quiroga
María F
MF
Department of Microbiology, Parasitology, and Immunology, University of Buenos Aires School of Medicine, Buenos Aires, Argentina.
Martínez
Gustavo J
GJ
Pasquinelli
Virginia
V
Costas
Mónica A
MA
Bracco
María M
MM
Malbrán
Alejandro
A
Olivares
Liliana M
LM
Sieling
Peter A
PA
García
Verónica E
VE
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology*; D015703:Antigens, CD; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D007424:Intracellular Fluid / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D047908:Intracellular Signaling Peptides and Proteins; D007918:Leprosy / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D009166:Mycobacterium leprae / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D011956:Receptors, Cell Surface; D050794:STAT1 Transcription Factor; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology*; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis; D000098815:T-bet Transcription Factor
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D002352:Carrier Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; C114953:SH2D1A protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn