Regulatory T Cells Control Th2-Dominant Murine Autoimmune Gastritis.
Pernicious anemia and gastric carcinoma are serious sequelae of autoimmune gastritis (AIG). Our study indicates that in adult C57BL/6-DEREG mice expressing a transgenic diphtheria toxin receptor under the Foxp3 promoter, transient regulatory T cell (Treg) depletion results in long-lasting AIG associated with both H(+)K(+)ATPase and intrinsic factor autoantibody responses. Although functional Tregs emerge over time during AIG occurrence, the effector T cells rapidly become less susceptible to Treg-mediated suppression. Whereas previous studies have implicated dysregulated Th1 cell responses in AIG pathogenesis, eosinophils have been detected in gastric biopsy specimens from patients with AIG. Indeed, AIG in DEREG mice is associated with strong Th2 cell responses, including dominant IgG1 autoantibodies, elevated serum IgE, increased Th2 cytokine production, and eosinophil infiltration in the stomach-draining lymph nodes. In addition, the stomachs exhibit severe mucosal and muscular hypertrophy, parietal cell loss, mucinous epithelial cell metaplasia, and massive eosinophilic inflammation. Notably, the Th2 responses and gastritis severity are significantly ameliorated in IL-4- or eosinophil-deficient mice. Furthermore, expansion of both Th2-promoting IFN regulatory factor 4(+) programmed death ligand 2(+) dendritic cells and ILT3(+) rebounded Tregs was detected after transient Treg depletion. Collectively, these data suggest that Tregs maintain physiological tolerance to clinically relevant gastric autoantigens, and Th2 responses can be a pathogenic mechanism in AIG.
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908; and jlh4zb@virginia.edu kst7k@virginia.edu.
Jessica
0000-0003-3523-2859
J
Harakal
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908; and Department of Pathology, University of Virginia, Charlottesville, VA 22908.
Claudia
C
Rival
Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908; and Department of Pathology, University of Virginia, Charlottesville, VA 22908.
Hui
0000-0002-2568-5144
H
Qiao
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908; and Department of Pathology, University of Virginia, Charlottesville, VA 22908 jlh4zb@virginia.edu kst7k@virginia.edu.
Kenneth S
0000-0002-9393-0084
KS
Tung
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D002478:Cells, Cultured; D005753:Gastric Mucosa / Q000276:immunology*; D005756:Gastritis / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D056747:Immunomodulation; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010295:Parietal Cells, Gastric / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D007074:Immunoglobulin G; D015847:Interleukin-4