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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

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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 1

OT-I cells and anti-OVA IgG synergistically induce diabetes.

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OT-I cells and anti-OVA IgG synergistically induce diabetes.
Diabetes in...
Diabetes incidence: RIP-mOVA mice were injected with 5 × 106 OT-I cells alone or together with administration of rabbit anti-OVA IgG, control rIgG, an F(ab′)2 fragment of rabbit anti-OVA IgG, or murine polyclonal anti-OVA IgG. Anti-OVA refers to rabbit anti-OVA IgG unless otherwise noted. Fractions below bars indicate the number of diabetic mice over the total number treated. Diabetes was not induced by transfer of OVA-specific antibodies and rarely by OT-I cells alone but was synergistically induced by transfer of both OT-I cells and anti-OVA IgG.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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