title: Anti-CD3 therapy promotes tolerance by selectively depleting pathogenic cells while preserving regulatory T cells.
abstract: Monoclonal anti-CD3 Abs have been used clinically for two decades to reverse steroid-resistant acute graft rejection. In autoimmune diabetes, short course treatment with FcR-nonbinding (FNB) anti-CD3 mAb in mice with recent onset of diabetes induces long-term disease remission. Induction of tolerogenic regulatory T cells (Tregs) has been implicated to be one of the mechanisms of action by FNB anti-CD3 mAb in these settings. In this study, we examined the effect of FNB anti-CD3 mAb treatment on the homeostasis of naive, effector, and regulatory T cells in vivo. Anti-CD3 treatment induced a transient systemic rise in the percentage but not absolute number of CD4(+)Foxp3(+) Tregs due to selective depletion of CD4(+)Foxp3(-) conventional T cells. T cell depletion induced by FNB anti-CD3 mAb was independent of the proapoptotic proteins Fas, caspase-3, and Bim and was not inhibited by overexpression of the anti-apoptotic protein, Bcl-2. Tregs were not preferentially expanded and we found no evidence of conversion of conventional T cells into Tregs, suggesting that the pre-existing Tregs are resistant to anti-CD3-induced cell death. Interestingly, expression of the transcription factor Helios, which is expressed by thymus-derived natural Tregs, was increased in Tregs after FNB anti-CD3 mAb treatment, suggesting that the anti-CD3 treatment can alter, and potentially stabilize, Treg function. Taken together, the results suggest that FNB anti-CD3 therapy promotes tolerance by restoring the balance between pathogenic and regulatory T cells.
authors: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Cristina
authors: C
authors: Penaranda
authors: Qizhi
authors: Q
authors: Tang
authors: Jeffrey A
authors: JA
authors: Bluestone
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017252:CD3 Complex; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000235:genetics; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C491746:Zfpn1a2 protein, mouse