Antibody-enhanced cross-presentation of self antigen breaks T cell tolerance.
We have developed a model of autoimmunity to investigate autoantibody-mediated cross-presentation of self antigen. RIP-mOVA mice, expressing OVA in pancreatic beta 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 (FcgammaRs) and cross-priming DCs. As a consequence, diabetes incidence and severity was reduced in mice lacking activating FcgammaRs. 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.
Harbers
Stephanie O
SO
Departments of Microbiology and Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, USA.
Crocker
Andrea
A
Catalano
Geoffrey
G
D'Agati
Vivette
V
Jung
Steffen
S
Desai
Dharmesh D
DD
Clynes
Raphael
R
D000818:Animals; D001323:Autoantibodies / Q000502:physiology*; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D045142:Cross-Priming / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D001323:Autoantibodies; D001324:Autoantigens