RESUMO
Loss-of-function variants of protein tyrosine phosphatase non-receptor type 2 (PTPN2) enhance risk of inflammatory bowel disease and rheumatoid arthritis; however, whether the association between PTPN2 and autoimmune arthritis depends on gut inflammation is unknown. Here we demonstrate that induction of subclinical intestinal inflammation exacerbates development of autoimmune arthritis in SKG mice. Ptpn2-haploinsufficient SKG mice - modeling human carriers of disease-associated variants of PTPN2 - displayed enhanced colitis-induced arthritis and joint accumulation of Tregs expressing RAR-related orphan receptor γT (RORγt) - a gut-enriched Treg subset that can undergo conversion into FoxP3-IL-17+ arthritogenic exTregs. SKG colonic Tregs underwent higher conversion into arthritogenic exTregs when compared with peripheral Tregs, which was exacerbated by haploinsufficiency of Ptpn2. Ptpn2 haploinsufficiency led to selective joint accumulation of RORγt-expressing Tregs expressing the colonic marker G protein-coupled receptor 15 (GPR15) in arthritic mice and selectively enhanced conversion of GPR15+ Tregs into exTregs in vitro and in vivo. Inducible Treg-specific haploinsufficiency of Ptpn2 enhanced colitis-induced SKG arthritis and led to specific joint accumulation of GPR15+ exTregs. Our data validate the SKG model for studies at the interface between intestinal and joint inflammation and suggest that arthritogenic variants of PTPN2 amplify the link between gut inflammation and arthritis through conversion of colonic Tregs into exTregs.
Assuntos
Artrite/genética , Doenças Autoimunes/genética , Proteínas de Ligação a DNA/genética , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Animais , Artrite/induzido quimicamente , Artrite/patologia , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/patologia , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Haploinsuficiência/genética , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Interleucina-17/genética , Intestinos/patologia , Articulações/metabolismo , Articulações/patologia , Mananas/toxicidade , Camundongos , Camundongos Knockout , Dodecilsulfato de Sódio/toxicidade , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologiaRESUMO
Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 inhibits signaling through the T cell and cytokine receptors, and loss of PTPN2 promotes T cell expansion and CD4- and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Tregs) plays a role in autoimmunity. Here we aimed to model human autoimmune-predisposing PTPN2 variants, the presence of which results in a partial loss of PTPN2 expression, in mouse models of RA. We identified that reduced expression of Ptpn2 enhanced the severity of autoimmune arthritis in the T cell-dependent SKG mouse model and demonstrated that this phenotype was mediated through a Treg-intrinsic mechanism. Mechanistically, we found that through dephosphorylation of STAT3, PTPN2 inhibits IL-6-driven pathogenic loss of FoxP3 after Tregs have acquired RORγt expression, at a stage when chromatin accessibility for STAT3-targeted IL-17-associated transcription factors is maximized. We conclude that PTPN2 promotes FoxP3 stability in mouse RORγt+ Tregs and that loss of function of PTPN2 in Tregs contributes to the association between PTPN2 and autoimmunity.