1,25(OH)2D3 Promotes the Efficacy of CD28 Costimulation Blockade by Abatacept.
Inhibition of the CD28:CD80/CD86 T cell costimulatory pathway has emerged as an effective strategy for the treatment of T cell-mediated inflammatory diseases. However, patient responses to CD28-ligand blockade by abatacept (CTLA-4-Ig) in conditions such as rheumatoid arthritis are variable and often suboptimal. In this study, we show that the extent to which abatacept suppresses T cell activation is influenced by the strength of TCR stimulation, with high-strength TCR stimulation being associated with relative abatacept insensitivity. Accordingly, cyclosporin A, an inhibitor of T cell stimulation via the TCR, synergized with abatacept to inhibit T cell activation. We also observed that 1,25-dihydroxyvitamin D3 enhanced the inhibition of T cell activation by abatacept, strongly inhibiting T cell activation driven by cross-linked anti-CD3, but with no effect upon anti-CD28 driven stimulation. Thus, like cyclosporin A, 1,25-dihydroxyvitamin D3 inhibits TCR-driven activation, thereby promoting abatacept sensitivity. Vitamin D3 supplementation may therefore be a useful adjunct for the treatment of conditions such as rheumatoid arthritis in combination with abatacept to promote the efficacy of treatment.
Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom;
David H
DH
Gardner
Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom;
Louisa E
LE
Jeffery
Institute of Immunity and Transplantation, University College London and Royal Free Hospital, London NW3 2PF, United Kingdom; and.
Blagoje
B
Soskic
Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom;
Zoe
Z
Briggs
Institute of Immunity and Transplantation, University College London and Royal Free Hospital, London NW3 2PF, United Kingdom; and.
Tie Zheng
TZ
Hou
Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Rheumatology, Sandwell and West Birmingham Hospitals National Health Service Trust, Birmingham B18 7QH, United Kingdom.
Karim
K
Raza
Institute of Immunity and Transplantation, University College London and Royal Free Hospital, London NW3 2PF, United Kingdom; and d.sansom@ucl.ac.uk.
David M
DM
Sansom
D000069594:Abatacept / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology; D018106:CD28 Antigens / Q000037:antagonists & inhibitors* / Q000276:immunology; D016466:CHO Cells; D002117:Calcitriol / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003412:Cricetulus; D016572:Cyclosporine / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D018106:CD28 Antigens; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept; D016572:Cyclosporine; D002117:Calcitriol