title: Anti-interleukin 10 receptor monoclonal antibody is an adjuvant for T helper cell type 1 responses to soluble antigen only in the presence of lipopolysaccharide.
abstract: Soluble foreign antigen usually leads to a transient clonal expansion of antigen-specific T cells followed by the deletion and/or functional inactivation of the cells. As interleukin (IL)-10 is a key immunoregulatory cytokine, we questioned whether neutralization of IL-10 during priming with soluble antigen could prime for a subsequent T helper cell type 1 (Th1) effector recall response. By using an adoptive transfer model to track the fate of antigen-specific T cell receptor (TCR)-transgenic CD4(+) T cells, we show that administration of soluble ovalbumin (OVA) protein, but not OVA(323-339) peptide antigen, together with an anti-IL-10 receptor (R) mAb led to the enhancement of a Th1 response upon rechallenge. Lipopolysaccharide (LPS) present in the protein was necessary for priming for Th1 recall responses in the presence of anti-IL-10R mAb, as removal of LPS abrogated this effect. Moreover, addition of LPS to the peptide did not itself allow priming for recall Th1 effector responses unless endogenous levels of IL-10 were neutralized with an anti-IL-10R mAb. A significant increase in OVA-specific IgG1 and IgG2a isotypes was observed when the protein antigen was administered with anti-IL-10R mAb; however, this was not the case with peptide antigen administered together with anti-IL-10R and LPS. Our data, showing that LPS receptor signaling and neutralization of endogenous immunosuppressive cytokines is essential for Th1 priming, has important implications for the design of relevant vaccines for effective in vivo immunotherapy.
authors.affiliation: Department of Immunology, DNAX Research Institute, Palo Alto, California 94304-1104, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Castro
authors.forename: M
authors.initials: M
authors.lastname: Neighbors
authors.forename: S D
authors.initials: SD
authors.lastname: Hurst
authors.forename: F
authors.initials: F
authors.lastname: Zonin
authors.forename: R A
authors.initials: RA
authors.lastname: Silva
authors.forename: E
authors.initials: E
authors.lastname: Murphy
authors.forename: Y J
authors.initials: YJ
authors.lastname: Liu
authors.forename: A
authors.initials: A
authors.lastname: O'Garra
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes; D004347:Drug Interactions; D007108:Immune Tolerance; D007156:Immunologic Memory; D008070:Lipopolysaccharides / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009500:Neutralization Tests; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D018123:Receptors, Interleukin / Q000276:immunology*; D053701:Receptors, Interleukin-10; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D010047:Ovalbumin