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The Inhibition of Autoreactive T Cell Functions by a Peptide Based on the CDR1 of an Anti-DNA Autoantibody Is via TGF--Mediated Suppression of LFA-1 and CD44 Expression and Function¹

Uri Sela^*,, Nora Mauermann^*, Rami Hershkoviz, Heidy Zinger^*, Molly Dayan^*, Liora Cahalon^*, Jian Ping Liu^*, Edna Mozes^2,* and Ofer Lider^3,*

^* Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; and Assaf-Harofeh Medical Center and Sakler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

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- secretion 10 days later. Addition of TGF- suppressed the 16/6Id-stimulated T cell proliferation similarly to hCDR1. In addition, we provide evidence that one possible mechanism underlying the hCDR1- and TGF-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 (L2) and CD44, which operate as accessory molecules in mediating APC-T cell interactions. Indeed, T cells of mice treated with hCDR1 showed a TGF--induced suppression of adhesion to the LFA-1 and CD44 ligands, hyaluronic acid and ICAM-1, respectively, induced by stromal cell-derived factor-1 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- on the expression and function of T cell adhesion receptors and, consequently, on T cell stimulation, adhesion, and proliferation.

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