title: An antibody against the surfactant protein A (SP-A)-binding domain of the SP-A receptor inhibits T cell-mediated immune responses to Mycobacterium tuberculosis.
abstract: Surfactant protein A (SP-A) suppresses lymphocyte proliferation and IL-2 secretion, in part, by binding to its receptor, SP-R210. However, the mechanisms underlying this effect are not well understood. Here, we studied the effect of antibodies against the SP-A-binding (neck) domain (alpha-SP-R210n) or nonbinding C-terminal domain (alpha-SP-R210ct) of SP-R210 on human peripheral blood T cell immune responses against Mycobacterium tuberculosis. We demonstrated that both antibodies bind to more than 90% of monocytes and 5-10% of CD3+ T cells in freshly isolated PBMC. Stimulation of PBMC from healthy tuberculin reactors [purified protein derivative-positive (PPD+)] with heat-killed M. tuberculosis induced increased antibody binding to CD3+ cells. Increased antibody binding suggested enhanced expression of SP-R210, and this was confirmed by Western blotting. The antibodies (alpha-SP-R210n) cross-linking the SP-R210 through the SP-A-binding domain markedly inhibited cell proliferation and IFN-gamma secretion by PBMC from PPD+ donors in response to heat-killed M. tuberculosis, whereas preimmune IgG and antibodies (alpha-SP-R210ct) cross-linking SP-R210 through the non-SP-A-binding, C-terminal domain had no effect. Anti-SP-R210n also decreased M. tuberculosis-induced production of TNF-alpha but increased production of IL-10. Inhibition of IFN-gamma production by alpha-SP-R210n was abrogated by the combination of neutralizing antibodies to IL-10 and TGF-beta1. Together, these findings support the hypothesis that SP-A, via SP-R210, suppresses cell-mediated immunity against M. tuberculosis via a mechanism that up-regulates secretion of IL-10 and TGF-beta1.
authors.affiliation: Department of Microbiology and Immunology, the Center for Pulmonary and Infectious Disease Control, the University of Texas Health Center, 11937 U.S. Hwy. 271, Tyler, TX 75708, USA. buka.samten@uthct.edu
authors.forename: Buka
authors.initials: B
authors.lastname: Samten
authors.forename: James C
authors.initials: JC
authors.lastname: Townsend
authors.forename: Zvjezdana
authors.initials: Z
authors.lastname: Sever-Chroneos
authors.forename: Virginia
authors.initials: V
authors.lastname: Pasquinelli
authors.forename: Peter F
authors.initials: PF
authors.lastname: Barnes
authors.forename: Zissis C
authors.initials: ZC
authors.lastname: Chroneos
mesh_terms: D000906:Antibodies / Q000494:pharmacology*; D000942:Antigens, Bacterial / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000276:immunology*; D009500:Neutralization Tests; D017434:Protein Structure, Tertiary; D037662:Pulmonary Surfactant-Associated Protein A / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D053773:Transforming Growth Factor beta1 / Q000276:immunology
chemical_list: D000906:Antibodies; D000942:Antigens, Bacterial; D016207:Cytokines; D037662:Pulmonary Surfactant-Associated Protein A; D011956:Receptors, Cell Surface; D053773:Transforming Growth Factor beta1; C067774:surfactant protein A receptor; D016753:Interleukin-10; D007371:Interferon-gamma