Antibody-enhanced cross-presentation of self antigen breaks T cell tolerance
Stephanie O. Harbers, Andrea Crocker, Geoffrey Catalano, Vivette D’Agati, Steffen Jung, Dharmesh D. Desai, Raphael Clynes
Stephanie O. Harbers, Andrea Crocker, Geoffrey Catalano, Vivette D’Agati, Steffen Jung, Dharmesh D. Desai, Raphael Clynes
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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 7

Antibody-enhanced OT-I cell proliferation and effector cell differentiation is dependent on activating Fcγ receptors.

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Antibody-enhanced OT-I cell proliferation and effector cell differentiat...
(A and B) OT-I cell proliferative responses in WT, FcγRγ–/–, and C3–/– mice. Flow cytometric analysis of pancreatic lymph node cells isolated from RIP-mOVA, RIP-mOVA FcγRγ–/–, and RIP-mOVA C3–/– mice (A) and ZVAD-treated and untreated RIP-mOVA C3–/– mice (B) 3 days after transfer of CFSE-labeled OT-I cells and anti-OVA IgG. The percentage of cells divided (A) and the numbers in the histogram (B) were calculated from FACS plots gated on CD8+CFSE+ cells found after the undivided peak. Bars show mean ± SD for at least 5 mice per treatment group. *P = 0.033; †0.0085; **P = 0.00040; #P = 0.00060; NS: P = 0.46. Histogram represents 1 of 2 independent experiments. Activating FcγRs were required for antibody-enhanced proliferation, whereas C3 negatively regulated T cell proliferation in a ZVAD-inhibitable manner. (C) OT-I cell effector differentiation in WT, FcγRγ–/–, and C3–/– mice. Intracellular IFN-γ staining of pancreatic lymph node cells isolated from mice 5 days after treatment. The percentage of cells producing IFN-γ was calculated from IFN-γ–positive cells among CD8+Vα2+Vβ5+-gated populations. Bars show mean ± SD for at least 3 mice per group. ***P = 1.06 × 10–6; ††P = 0.00048; ##P = 0.016; ζP = 0.037; NS: P = 0.28. Antibody enhancement of IFN-γ production was intact in C3–/– but not FcγRγ–/– mice.