title: Antigen-specific signaling by a soluble, dimeric peptide/major histocompatibility complex class II/Fc chimera leading to T helper cell type 2 differentiation.
abstract: Interaction between a T cell receptor (TCR) and various ligands, i.e. , anti-TCR antibodies, superantigens, peptides, or altered peptide ligands in the context of major histocompatibility complex (MHC) molecules can trigger different T helper cell (Th) effector functions. Herein, we studied the T cell response induced by a soluble, dimeric peptide/MHC class II chimera, namely hemagglutinin (HA)110-120/I-E(d)alphabeta/Fcgamma2a (DEF). We have previously demonstrated that the soluble DEF molecule binds stably and specifically to HA110-120-specific TCRs expressed by a T cell hybridoma. Administration of DEF in vivo induced differentiation of resting and activated peptide-specific T cells toward a Th2 response, as indicated by the increase of interleukin (IL)-4, IL-10, and specific immunoglobulin (Ig)G1 antibodies and decrease of IL-2, specific IgG2a antibodies, and cytotoxic T lymphocyte activity. In contrast to HA110-120 peptide presented by the DEF molecule to T cells, the nominal synthetic peptide induced a predominant Th1 response, and the PR8 virus-derived HA110-120 peptides induced a mixed Th1/Th2 response. Independent of antigen processing, soluble DEF was almost 2 logs more potent in stimulating cognate T cells than the nominal peptide. Polarization of cognate T cells toward the Th2 response occurred upon interaction of soluble DEF with TCR and CD4 molecules followed by early activation of p56(lck) and ZAP-70 tyrosine kinases, and negative signaling of the signal transducer and activator of transcription (STAT)4 pathway of Th1 differentiation. DEF-like molecules may provide a new tool to study the mechanisms of signaling toward Th2 differentiation and may also provide a potential immunotherapeutic approach to modulate autoreactive T cells toward protective Th2 immune responses.
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: S
authors.initials: S
authors.lastname: Casares
authors.forename: C S
authors.initials: CS
authors.lastname: Zong
authors.forename: D L
authors.initials: DL
authors.lastname: Radu
authors.forename: A
authors.initials: A
authors.lastname: Miller
authors.forename: C A
authors.initials: CA
authors.lastname: Bona
authors.forename: T D
authors.initials: TD
authors.lastname: Brumeanu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation; D004268:DNA-Binding Proteins; D019281:Dimerization; D006388:Hemagglutinins; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D012995:Solubility; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*; D015534:Trans-Activators
chemical_list: D004268:DNA-Binding Proteins; D006388:Hemagglutinins; D000949:Histocompatibility Antigens Class II; D007141:Immunoglobulin Fc Fragments; D007376:Interleukin-2; D009842:Oligopeptides; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D016753:Interleukin-10; D015847:Interleukin-4