Inhibition of T cell activation and autoimmune diabetes using a B cell surface–linked CTLA-4 agonist
Brian T. Fife, Matthew D. Griffin, Abul K. Abbas, Richard M. Locksley, Jeffrey A. Bluestone
Brian T. Fife, Matthew D. Griffin, Abul K. Abbas, Richard M. Locksley, Jeffrey A. Bluestone
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Research Article Immunology

Inhibition of T cell activation and autoimmune diabetes using a B cell surface–linked CTLA-4 agonist

Abstract

CTL-associated antigen 4 (CTLA-4) engagement negatively regulates T cell activation and function and promotes immune tolerance. However, it has been difficult to explore the biology of selective engagement of CTLA-4 in vivo because CTLA-4 shares its ligands, B7-1 and B7-2, with CD28. To address this issue, we developed a Tg mouse expressing a single-chain, membrane-bound anti–CTLA-4 Ab (scFv) on B cells. B and T cells developed normally and exhibited normal phenotype in the steady state and after activation in these mice. However, B cells from scFv Tg+ mice (scαCTLA4+) prevented T cell proliferation and cytokine production in mixed lymphocyte reactions. Additionally, mice treated with scαCTLA4+ B cells had decreased T cell–dependent B cell Ab production and class switching in vivo after antigen challenge. Furthermore, expression of this CTLA-4 agonist protected NOD mice from spontaneous autoimmune diabetes. Finally, this disease prevention occurred in Treg-deficient NOD.B7-1/B7-2 double-knockout mice, suggesting that the effect of the CTLA-4 agonist directly attenuates autoreactive T cell activation, not Treg activation. Together, results from this study demonstrate that selective ligation of CTLA-4 attenuates in vivo T cell responses, prevents development of autoimmunity, and represents a novel immunotherapeutic approach for the induction and maintenance of peripheral tolerance.

Authors

Brian T. Fife, Matthew D. Griffin, Abul K. Abbas, Richard M. Locksley, Jeffrey A. Bluestone

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Figure 7

scαCTLA-4 Tg+ NOD. B7 DKO mice are protected from accelerated diabetes.

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scαCTLA-4 Tg+ NOD. B7 DKO mice are ...
Female NOD.B7 DKO and NOD.B7 DKO.scαCTLA-4 Tg+ mice were monitored for the development of spontaneous disease. (A) Diabetes incidence is shown here for NOD.B7 DKO (n = 12) (open circles) and NOD.B7 DKO.scαCTLA-4 Tg+ mice (n = 20) (filled circles). NOD.B7 DKO diabetes incidence reached 100% while diabetes incidence in NOD.B7 DKO.scαCTLA-4 Tg+ mice was significantly reduced to 60% by 30 weeks of age (P < 0.003). (B) NOD.B7 DKO.scαCTLA-4 Tg+ mice have decreased insulitis at 14 weeks of age. Pancreas from 14-week-old NOD.B7 DKO and scαCTLA-4 Tg NOD.B7 DKO mice were stained with H&E to determine clinical severity of insulitis. Pancreatic islets were scored for the presence of mononuclear infiltration: 0, no infiltrate; 1, peri-insulitis present; 2, 25–50% of the islet contained infiltrate; 3, more than 50% of the islet was infiltrated. Average percentages shown were determined from at least 100 islets from at least 3 mice per group. (C) Flow cytometric analysis was performed to determine the percentage of CD4+CD25+CD62L+ and (D) CD4+CD25+FoxP3+ Tregs in the lymphoid tissue of NOD.B7 DKO, NOD. B7 DKO.scαCTLA-4 Tg+, and NOD mice. The mean ± SD from at least 3 mice per group is shown. Results shown are representative of 3 independent experiments.