Regulation of cellular homeostasis by NTB-A-SAP pathway in tuberculosis.

RODRIGO HERNÁNDEZ DEL PINO; ANA INÉS ROVETTA; GUADALUPE INÉS ALVAREZ; DELFINA PEÑA; ROSA MUSELLA; DOMINGO PALMERO; ALEJANDRO MALBRÁN; VIRGINIA PASQUINELLI; VERÓNICA GARCÍA

Córdoba

Taller; First Argentinean Spring Course in Advanced Immunology; 2013

Sociedad Argentina de Inmunología (SAI).

NK, T, and B cell antigen (NTB-A) and SLAM associated protein (SAP) expression is required for T cell restimulation-induced cell death (RICD). X-linked lymphoproliferative (XLP) patients present a SAP inactivating mutation which causes a severe primary immunodeficiency. T cells from these patients produce high IFNg levels and are resistant to RICD. Previously, we reported that SAP interferes with M. tuberculosis (Mtb)-induced IFNg production. We investigated the role of the NTB-A/SAP pathway in the regulation of lymphocyte homeostasis on XLP individuals, healthy donors (HD) and tuberculosis (TB) patients (classified as Low and High responders (LR and HR) according to immune responses and disease severity). Significant increases on SAP mRNA levels were found after 5 days of Mtb stimulation (p<0.05) and inversely correlated with IFNg production. To address whether SAP is directly required for RICD, we evaluated cell loss in restimulated cells. Between 35-50% of XLP patient T-cells undergo apoptosis after restimulation, while HD and HR patients showed 70-90% of cell loss (p<0.05). Surprisingly, LR patients had similar levels of cell loss to XLP individuals. NTB-A blockage decreased HD and HR RICD to 30% but no changes were observed in XLP and LR patients. To evaluate the mechanisms involved in LR RICD inhibition, we analyzed cell proliferation, IL-2 and CD25 expression after re-stimulation with/without anti-NTB-A in TB patients and HD, but we did not found any modulation by NTB-A. Moreover, XLP patients had the lowest TNF-a levels, but the lower RICD in LR was not due to differential TNF-a regulation. NTB-A induced IFNg and IL-17 in Mtb-stimulated cells but not in cells with a re-stimulation protocol. These results demonstrate that NTB-A induces pro-inflammatory responses during T activation/differentiation and regulates the homeostasis of the immune response against Mtb through RICD induction in HR patients and HD, but that the lack of response of LR patients is not due to an increased RICD.