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 3

In vitro activation of B cells and T cells from scαCTLA-4 Tg+ mice.

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In vitro activation of B cells and T cells from scαCT...
(A) B and T cell proliferation was assessed from scαCTLA-4 Tg+ and controls using splenocytes following 0, 0.1, 1, or 10 μg/ml (A) anti-IgM, (B) LPS, or (C) anti-CD3 stimulation. (D) Flow cytometric analysis from scαCTLA-4 Tg+ and FVB controls after 48-hour culture with anti-IgM (1 μg/ml). Shaded histogram represents positive stain for B7-1, B7-2, CD40, and MHC II. Percentage positive above isotype control with mean fluorescence intensity (ΔMFI) is shown. Histograms are gated on B220+ cells. Data presented are representative of 3 independent experiments with ≥ 3 mice per group.