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 5

scαCTLA-4 Tg+ B cells inhibit T cell–dependent B cell IgG2a Ab production in vivo.

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scαCTLA-4 Tg+ B cells inhibit T cel...
scαCTLA-4 Tg and FVB littermate control B cells were activated in the presence of LPS (1 μg/ml) for 72 hours, loaded with DNP-OVA, and transferred to naive FVB recipients. Seven days following transfer of cells, recipient animals were boosted with 100 μg DNP-OVA in CFA injected subcutaneously. Fourteen days following B cell transfer, anti-DNP Ab production was measured using DNP-KLH–specific ELISA. Shown in A, anti-DNP serum IgG2a from 4 individual WT or scαCTLA-4 Tg+–treated mice. (B) Anti-DNP serum IgG1 from 4 individual WT or scαCTLA-4 Tg+–treated mice. (C) Total Ig from 10 individual WT or scαCTLA-4 Tg+–treated mice. The mean for each group is shown with a horizontal line. Results shown are representative of at least 2 independent experiments.