title: PTPN2-deficiency exacerbates T follicular helper cell and B cell responses and promotes the development of autoimmunity.
abstract: Non-coding single nucleotide polymorphisms that repress PTPN2 expression have been linked with the development of type 1 diabetes, rheumatoid arthritis and Crohn's disease. PTPN2 attenuates CD8+T cell responses to self and prevents overt autoreactivity in the context of T cell homeostasis and antigen cross-presentation. The role of PTPN2 in other immune subsets in the development of autoimmunity remains unclear. Here we show that the inducible deletion of PTPN2 in hematopoietic compartment of adult non-autoimmune prone mice results in systemic inflammation and autoimmunity. PTPN2-deficient mice had increased inflammatory monocytes, B cells and effector T cells in lymphoid and non-lymphoid tissues and exhibited symptoms of dermatitis, glomerulonephritis, pancreatitis and overt liver disease. Autoimmunity was characterised by the formation of germinal centers in the spleen and associated with markedly increased germinal center B cells and T follicular helper (Tfh) cells and circulating anti-nuclear antibodies, inflammatory cytokines and immunoglobulins. CD8+T cell proliferative responses were enhanced, and interleukin-21-induced STAT-3 signalling in Tfhcells and B cells was increased and accompanied by enhanced B cell proliferation ex vivo. These results indicate that deficiencies in PTPN2 across multiple immune lineages, including naive T cells, Tfhcells and B cells, contribute to the development of autoimmunity.
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia.
authors.forename: Florian
authors.initials: F
authors.lastname: Wiede
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia.
authors.forename: Faruk
authors.initials: F
authors.lastname: Sacirbegovic
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia.
authors.forename: Yew Ann
authors.initials: YA
authors.lastname: Leong
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia.
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia. Electronic address: Tony.Tiganis@monash.edu.
authors.forename: Tony
authors.initials: T
authors.lastname: Tiganis
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000172:deficiency*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism*; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D050796:STAT3 Transcription Factor; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D000098546:Interleukin-21
keywords: Autoimmunity; B cell; Hematopoiesis; Inflammation; PTPN2; T(fh) cell