Expression of Signaling Lymphocytic Activation Molecule- Associated Protein Interrupts IFN-γ Production in Human Tuberculosis

Pasquinelli, Virginia; Quiroga, María Florencia; Martínez, Gustavo; Zorrilla, Liliana Castro; Musella, Rosa M.; Bracco, M; Belmonte, Liliana; Malbrán, Alejandro; Fainboim, Leonardo; Sieling, Peter A.; García, Verónica

doi:10.4049/jimmunol.172.2.1177

Cited by 36 publications

(143 citation statements)

References 27 publications

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“…1A). These data, indicating that the expression of SAP is lowest in the group of patients who displayed high immune responses to M. leprae, that is Th1-type immune responses, are in accord with our findings in tuberculosis (15) and suggest that the expression of SAP interferes with Th1 responses during mycobacterial infection.…”

Section: Expression Of Sap In Leprosy Patients Correlates With Increasupporting

confidence: 80%

“…Because signaling through the costimulatory molecule SLAM enhanced IFN-␥ production in leprosy patients (14), we investigated at the molecular level the alternative pathway triggered by SLAM that leads to IFN-␥ production in human leprosy. The existence of an inverse relationship between SAP expression and IFN-␥ production by Ag-stimulated T cells in tuberculosis and XLP patients (15) indicates that SAP attenuates Th1 immune responses (7,15). In fact, we showed that SAP turns off IFN-␥ production in L-Lep patients, but stimulation with SLAM and TCR together decreased SAP expression in unresponsive patients.…”

Section: Discussionmentioning

confidence: 59%

“…In contrast, SAP interrupts IFN-␥ production in tuberculosis (15). Therefore, we investigated at the molecular level the pathways leading from SLAM ligation to IFN-␥ production during M. leprae infection.…”

Section: Expression Of Sap In Leprosy Patients Correlates With Increamentioning

confidence: 99%

“…PMBCs were stimulated as described above; thereafter, cells were washed and solubilized in lysis buffer (50 mM Tris (pH 8), 1% Nonidet P-40, 200 mM NaCl, 10% glycerol, 0,5 mM EDTA, and Protease Inhibitor Cocktail (Sigma-Aldrich)) to prepare whole cell extracts as previously described (15). Immunoprecipitation experiments were performed as described previously (20).…”

Section: Western Blot and Immunoprecipitationmentioning

confidence: 99%

“…Then, restoring IFN-␥ production in leprosy patients to reverse disseminated mycobacterial infection might be achieved through ligation of pathways that stimulate IFN-␥ production. Engagement of SLAM enhances IFN-␥ production in mycobacterial infection, even in Ag-unresponsive patients (14,15), whereas SAP expression in cells from tuberculosis patients is inversely correlated with IFN-␥ production (15). Therefore, in this study we investigated molecular pathways leading from SLAM ligation to IFN-␥ production in human leprosy.…”

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confidence: 99%

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

Quiroga

Martínez

Pasquinelli

et al. 2004

The Journal of Immunology

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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.

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Section: Expression Of Sap In Leprosy Patients Correlates With Increasupporting

confidence: 80%

Section: Discussionmentioning

confidence: 59%

Section: Expression Of Sap In Leprosy Patients Correlates With Increamentioning

confidence: 99%

Section: Western Blot and Immunoprecipitationmentioning

confidence: 99%

mentioning

confidence: 99%

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

Quiroga

Martínez

Pasquinelli

et al. 2004

The Journal of Immunology

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SLAMF1 signaling induces Mycobacterium tuberculosis uptake leading to endolysosomal maturation in human macrophages

Barbero

Trotta

Genoula

et al. 2020

Journal of Leukocyte Biology

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Tuberculosis dates back to ancient times but it is not a problem of the past. Each year, millions of people die from tuberculosis. After inhalation of infectious droplet nuclei, Mycobacterium tuberculosis reaches the lungs where it can manipulate the immune system and survive within host macrophages, establishing a persistent infection. The signaling lymphocytic activation molecule family member 1 (SLAMF1) is a self-ligand receptor that can internalize gram-negative bacteria and regulate macrophages' phagosomal functions. In tuberculosis, SLAMF1 promotes Th1-protective responses. In this work, we studied the role of SLAMF1 on macrophages' functions during M. tuberculosis infection. Our results showed that both M. tuberculosis and IFNstimulation induce SLAMF1 expression in macrophages from healthy donor and Tohoku Hospital Pediatrcs-1 cells. Costimulation through SLAMF1 with an agonistic antibody resulted in an enhanced internalization of M. tuberculosis by macrophages. Interestingly, we found that SLAMF1 interacts with M. tuberculosis and colocalizes with the bacteria and with early and late endosomes/lysosomes markers (EEA1 and LAMP2), suggesting that SLAMF1 recognize M. tuberculosis and participate in the endolysosomal maturation process. Notably, increased levels of SLAMF1 were detected in CD14 cells from pleural effusions of tuberculosis patients, indicating that SLAMF1 might have an active function at the site of infection. Taken together, our results provide evidence that SLAMF1 improves the uptake of M. tuberculosis by human monocyte-derived macrophages.

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The Impact of IFN-γ Receptor on SLPI Expression in Active Tuberculosis

Tateosian

Pasquinelli

Pino

et al. 2014

The American Journal of Pathology

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Interferon (IFN)-γ displays a critical role in tuberculosis (TB), modulating the innate and adaptive immune responses. Previously, we reported that secretory leukocyte protease inhibitor (SLPI) is a pattern recognition receptor with anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb). Herein, we determined whether IFN-γ modulated the levels of SLPI in TB patients. Plasma levels of SLPI and IFN-γ were studied in healthy donors (HDs) and TB patients. Peripheral blood mononuclear cells from HDs and patients with TB or defective IFN-γ receptor 1* were stimulated with Mtb antigen and SLPI, and IFN-γR expression levels were measured. Both SLPI and IFN-γ were significantly enhanced in plasma from those with TB compared with HDs. A direct association between SLPI levels and the severity of TB was detected. In addition, Mtb antigen stimulation decreased the SLPI produced by peripheral blood mononuclear cells from HDs, but not from TB or IFN-γR patients. Neutralization of IFN-γ reversed the inhibition of SLPI induced by Mtb antigen in HDs, but not in TB patients. Furthermore, recombinant IFN-γ was unable to modify the expression of SLPI in TB patients. Finally, IFN-γR expression was lower in TB compared with HD peripheral blood mononuclear cells. These results show that Mtb-induced IFN-γ down-modulated SLPI levels by signaling through the IFN-γR in HDs. This inhibitory mechanism was not observed in TB, probably because of the low expression of IFN-γR detected in these individuals.

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Expression of Signaling Lymphocytic Activation Molecule- Associated Protein Interrupts IFN-γ Production in Human Tuberculosis

Cited by 36 publications

References 27 publications

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

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

SLAMF1 signaling induces Mycobacterium tuberculosis uptake leading to endolysosomal maturation in human macrophages

The Impact of IFN-γ Receptor on SLPI Expression in Active Tuberculosis

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