Antibody ligation of the SP-A receptor SP-R210 inhibits IFN-g production in response to M. tuberculosis

BUKA SAMTEN; JAMES C. TOWNSEND; ZVJEZDANA SEVER-CHRONEOS; VIRGINIA PASQUINELLI; PETER F. BARNES; ZISSIS C. CHRONEOS

Toronto

Congreso; American Thoracic Society, International Conference; 2008

American Thoracic Society

Tuberculosis remains as a leading cause of morbidity and mortality worldwide. The role of local host factors in the pathogenesis of tuberculosis is not understood. Surfactant protein A (SP-A) modulates innate and adaptive immune cells responding to airborne pathogens. Specifically, the SP-A receptor SP-R210 was implicated in suppression of lymphocyte proliferation. Here, we tested whether SP-R210 modulates adaptive immune responses in human peripheral blood mononuclear cells (PBMC) from healthy tuberculin reactors. Flow cytometry revealed SP-R210 expression on >90% of CD14+ monocytes and 5-10% of CD3+ T-lymphocytes in un-stimulated PBMC. Expression of SP-R210 increased 5-8-fold on CD3+ lymphocytes 24-48 hr after stimulation of PBMC with M. tuberculosis. These results were confirmed by Western blot analysis. To address the biological significance of these findings we tested the effect of domain-specific SPR210 antibodies on lymphocyte proliferation and cytokine secretion following challenge of PBMC with heatkilled M. tuberculosis. We demonstrate that antibodies ligating the SP-A binding domain of SP-R210, SPR210n, inhibit M. tuberculosis-induced lymphocyte proliferation and expression of IFN-g in PBMC from healthy tuberculin reactors, whereas pre-immune antibodies and antibodies recognizing the non-SP-A binding SP-R210ct domain had no effect. Furthermore, SP-R210n antibodies decreased M. tuberculosis induced production of TNF but increased production of IL-10. The inhibition of IFN production by anti-SPR210n was abrogated by the combination of neutralizing antibodies to IL-10 and transforming growth factor (TGF)-b . Together, these findings support the concept that SP-A, via SP-R210, suppresses cell-mediated immunity in tuberculosis via a mechanism that involves elaboration of IL-10 and TGF-b.