Transition from an autoimmune-prone state to fatal autoimmune disease in CCR7 and RORγt double-deficient mice is dependent on gut microbiota.
Autoimmunity is associated with a strong genetic component, but onset and persistence of clinically apparent autoimmune diseases often require an additional environmental trigger. The balance between immunity and tolerance is regulated by numerous molecular factors including nuclear hormone and homeostatic chemokine receptors. The nuclear hormone receptor RORγt and the chemokine receptor CCR7 are both essentially involved in functional lymphoid organogenesis and maintenance of lymphocyte homeostasis. Lack of one or the other impairs thymic T cell development and alters T cell homeostasis. Mice deficient for both, Ccr7(-/-)Rorγt(-/-), succumbed early to acute destructive inflammation, characterized by massive recruitment of inflammatory leukocytes, pro-inflammatory cytokine and autoantibody production, and wasting disease. Antibiotic-treatment of mice before disease onset reduced the overall gut microflora and abrogated the development of fatal mucosal inflammation. Hence, commensal bacteria and a confined tissue-specific inflammatory milieu serve as complementary trigger to initiate the lethal pathophysiologic process in Ccr7(-/-)Rorγt(-/-) mice.
Max-Delbrück-Center for Molecular Medicine, MDC, Department of Tumor Genetics and Immunogenetics, Berlin 13125, Germany.
Katharina
K
Wichner
André
A
Fischer
Susann
S
Winter
Solveig
S
Tetzlaff
Markus M
MM
Heimesaat
Stefan
S
Bereswill
Armin
A
Rehm
Martin
M
Lipp
Uta E
UE
Höpken
D000667:Ampicillin / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002678:Chimera / Q000276:immunology; D003091:Colistin / Q000627:therapeutic use; D007249:Inflammation / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology*; D007962:Leukocytes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics*; D054400:Receptors, CCR7 / Q000235:genetics*; D013307:Streptomycin / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D001323:Autoantibodies; C515371:Ccr7 protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D054400:Receptors, CCR7; D000667:Ampicillin; D013307:Streptomycin; D003091:Colistin
CCR7/RORγt double-deficient; DKO; Gut microbiota; Homeostatic chemokine receptor; ILFs; LTis; Mucosal inflammation; Retinoic acid receptor-related orphan receptor; SLO; Thymic T cell development; Tregs; isolated lymphoid follicles; lymphoid tissue inducer cells; regulatory T cells; secondary lymphoid organ