Antibody-enhanced cross-presentation of self antigen breaks T cell tolerance
Stephanie O. Harbers, … , Dharmesh D. Desai, Raphael Clynes
Stephanie O. Harbers, … , Dharmesh D. Desai, Raphael Clynes
Published May 1, 2007
Citation Information: J Clin Invest. 2007;117(5):1361-1369. https://doi.org/10.1172/JCI29470.
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Research Article Autoimmunity

Antibody-enhanced cross-presentation of self antigen breaks T cell tolerance

Abstract

We have developed a model of autoimmunity to investigate autoantibody-mediated cross-presentation of self antigen. RIP-mOVA mice, expressing OVA in pancreatic β cells, develop severe autoimmune diabetes when given OT-I cells (OVA-specific CD8+ T cells) and anti-OVA IgG but not when given T cells alone. Anti-OVA IgG is not directly injurious to the islets but rather enhances cross-presentation of apoptotic islet antigen to the OT-I cells, leading to their differentiation into potent effector cells. Antibody-driven effector T cell activation is dependent on the presence of activating Fc receptors for IgG (FcγRs) and cross-priming DCs. As a consequence, diabetes incidence and severity was reduced in mice lacking activating FcγRs. An intact complement pathway was also required for disease development, as C3 deficiency was also partially protective. C3-deficient animals exhibited augmented T cell priming overall, indicating a proinflammatory role for complement activation after the T cell priming phase. Thus, we show that autoreactive antibody can potently enhance the activation of effector T cells in response to cross-presented self antigen, thereby contributing to T cell–mediated autoimmunity.

Authors

Stephanie O. Harbers, Andrea Crocker, Geoffrey Catalano, Vivette D’Agati, Steffen Jung, Dharmesh D. Desai, Raphael Clynes

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Figure 6

Mice lacking activating Fcγ receptors and complement are protected from severe antibody-induced diabetes.

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Mice lacking activating Fcγ receptors and complement are protected from ...
(A) Diabetes incidence. RIP-mOVA, RIP-mOVA FcγRγ–/–, RIP-mOVA C3–/–, and RIP-mOVA FcγRγ–/–C3–/– mice were injected with 5 × 106 OT-I cells alone or together with 1,000 μg anti-OVA IgG. Fractions below bars indicate the number of diabetic mice over the total number treated. Diabetes occurred in 100% of antibody-treated WT RIP-mOVA mice compared with 41% of FcγRγ–/–, 35% of C3–/–, and 0% of FcγRγ–/–C3–/– mice (P = 2 × 10–6, 5 × 10–7, and 8 × 10–10, respectively). (B) Survival of WT, FcγRγ–/–, and C3–/– mice. Kaplan-Meier curves of RIP-mOVA mice (black) compared with RIP-mOVA FcγRγ–/– mice (gray, left) and RIP-mOVA C3–/– mice (gray, right) after transfer of OT-I cells and anti-OVA IgG (***P = 1 × 10–4). Diabetes was severe and usually lethal in WT mice. In contrast, disease severity was attenuated in FcγRγ–/– and C3–/– mice, with no mice developing fatal diabetes.