title: Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis.
abstract: The ultimate goal for the treatment of autoimmunity is to restore immunological tolerance. Regulatory T cells (Treg) play a central role in immune tolerance, and Treg functional abnormalities have been identified in different autoimmune diseases, including rheumatoid arthritis (RA). We have previously shown that natural Treg from RA patients are competent at suppressing responder T cell proliferation but not cytokine production. Here, we explore the hypothesis that this Treg defect in RA is linked with abnormalities in the expression and function of CTLA-4. We demonstrate that CTLA-4 expression on Treg from RA patients was significantly reduced compared with healthy Treg and is associated with an increased rate of CTLA-4 internalization. Regulation of T cell receptor signaling by CTLA-4 was impaired in RA Treg and associated with delayed recruitment of CTLA-4 to the immunological synapse. Artificial induction of CTLA-4 expression on RA Treg restored their suppressive capacity. Furthermore, CTLA-4 blockade impaired healthy Treg suppression of T cell IFN-gamma production, but not proliferation, thereby recapitulating the unique Treg defect in RA. Our results suggest that defects in CTLA-4 could contribute to abnormal Treg function in RA and may represent a target for therapy for inducing long-lasting remission.
authors.affiliation: Centre for Rheumatology, Division of Medicine, Windeyer Institute of Medical Sciences, University College London, London W1T 4JF, United Kingdom.
authors.forename: Fabian
authors.initials: F
authors.lastname: Flores-Borja
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Jury
authors.forename: Claudia
authors.initials: C
authors.lastname: Mauri
authors.forename: Michael R
authors.initials: MR
authors.lastname: Ehrenstein
mesh_terms: D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D020381:Interleukin-17 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D011948:Receptors, Antigen, T-Cell