title: The inhibition of autoreactive T cell functions by a peptide based on the CDR1 of an anti-DNA autoantibody is via TGF-beta-mediated suppression of LFA-1 and CD44 expression and function.
abstract: Systemic lupus erythematosus (SLE), which is characterized by the increased production of autoantibodies and defective T cell responses, can be induced in mice by immunization with a human anti-DNA mAb that expresses a major Id, designated 16/6Id. A peptide based on the sequence of the CDR1 of the 16/6Id (human CDR1 (hCDR1)) ameliorated the clinical manifestations of SLE and down-regulated, ex vivo, the 16/6Id-induced T cell proliferation. In this study, we examined the mechanism responsible for the hCDR1-induced modulation of T cell functions related to the pathogenesis of SLE. We found that injection of hCDR1 into BALB/c mice concomitant with their immunization with 16/6Id resulted in a marked elevation of TGF-beta secretion 10 days later. Addition of TGF-beta suppressed the 16/6Id-stimulated T cell proliferation similarly to hCDR1. In addition, we provide evidence that one possible mechanism underlying the hCDR1- and TGFbeta-induced inhibition of T cell proliferation is by down-regulating the expression, and therefore the functions, of a pair of key cell adhesion receptors, LFA-1 (alphaLbeta2) and CD44, which operate as accessory molecules in mediating APC-T cell interactions. Indeed, T cells of mice treated with hCDR1 showed a TGF-beta-induced suppression of adhesion to the LFA-1 and CD44 ligands, hyaluronic acid and ICAM-1, respectively, induced by stromal cell-derived factor-1alpha and PMA. The latter suppression is through the inhibition of ERK phosphorylation. Thus, the down-regulation of SLE-associated responses by hCDR1 treatment may be due to the effect of the up-regulated TGF-beta on the expression and function of T cell adhesion receptors and, consequently, on T cell stimulation, adhesion, and proliferation.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Sela
authors.forename: Nora
authors.initials: N
authors.lastname: Mauermann
authors.forename: Rami
authors.initials: R
authors.lastname: Hershkoviz
authors.forename: Heidy
authors.initials: H
authors.lastname: Zinger
authors.forename: Molly
authors.initials: M
authors.lastname: Dayan
authors.forename: Liora
authors.initials: L
authors.lastname: Cahalon
authors.forename: Jian Ping
authors.initials: JP
authors.lastname: Liu
authors.forename: Edna
authors.initials: E
authors.lastname: Mozes
authors.forename: Ofer
authors.initials: O
authors.lastname: Lider
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D049109:Cell Proliferation; D022801:Complementarity Determining Regions / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology* / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism; D007130:Immunoglobulin Idiotypes; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism
chemical_list: D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; C476399:Cd44 protein, mouse; D022801:Complementarity Determining Regions; D018960:Hyaluronan Receptors; D007130:Immunoglobulin Idiotypes; D016169:Lymphocyte Function-Associated Antigen-1; D010455:Peptides; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D006820:Hyaluronic Acid