title: On the mechanisms by which transforming growth factor-beta 2 alters antigen-presenting abilities of macrophages on T cell activation.
abstract: Peritoneal exudate cells (PEC) incubated with antigen in the presence of transforming growth factor-(TGF)-beta 2 selectively suppress delayed hypersensitivity and IgG2a antibody production when injected intravenously into naive syngeneic recipients. In this study, we have examined in vitro the effects of TGF-beta 2 on the antigen presenting abilities of PEC to activate DO11.10 T cells that express a transgenic T cell receptor that recognizes ovalbumin peptide fragment 323-339 in the context of I-Ad. PEC were pretreated overnight with TGF-beta 2, washed extensively, then co-cultured with DO11.10 T cells in the presence of native OVA or P323-339. We found that TGF-beta 2-treated PEC induced the production of the T helper type 2 (Th2) cytokine, interleukin-4 (IL-4), but unlike untreated PEC, were unable to stimulate the Th1 cytokines, IL-2 and interferon-gamma (IFN-gamma). Furthermore, TGF-beta 2 was produced in an autocrine fashion by TGF-beta 2-treated PEC and was responsible for this shift to a Th2 response. This conclusion was supported by the following results. First, TGF-beta 2-treated PEC were found to express much more TGF-beta 1 and TGF-beta 2 mRNA than untreated PEC. Second, TGF-beta 2-treated PEC secreted large amounts of TGF-beta including its mature form. Third, addition of neutralizing anti-TGF-beta 2 antibodies, but not neutralizing anti-TGF-beta 1 antibodies, restored the ability of antigen-pulsed, TGF-beta 2-pretreated PEC to stimulate DO11.10 T cells to secrete IL-2 and IFN-gamma. These results indicate that antigen-presenting cells that encounter antigen in a TGF-beta-enriched environment (e.g., in the eye) shift responding native T cells toward Th2 responses by producing TGF-beta during antigen presentation.
authors.affiliation: Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: M
authors.initials: M
authors.lastname: Takeuchi
authors.forename: M M
authors.initials: MM
authors.lastname: Kosiewicz
authors.forename: P
authors.initials: P
authors.lastname: Alard
authors.forename: J W
authors.initials: JW
authors.lastname: Streilein
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002474:Cell-Free System / Q000737:chemistry / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D006131:Growth Inhibitors / Q000032:analysis; D016056:Immunodominant Epitopes / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*
chemical_list: D000906:Antibodies; D016207:Cytokines; D006131:Growth Inhibitors; D016056:Immunodominant Epitopes; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D010047:Ovalbumin