title: PTPN22 controls virally-induced autoimmune diabetes by modulating cytotoxic T lymphocyte responses in an epitope-specific manner.
abstract: Ptpn22 is one of the most potent autoimmunity predisposing genes and strongly associates with type 1 diabetes (T1D). Previous studies showed that non-obese diabetic mice with reduced expression levels of Ptpn22 are protected from T1D due to increased number of T regulatory (Treg) cells. We report that lack of Ptpn22 exacerbates virally-induced T1D in female rat insulin promoter lymphocytic choriomeningitis virus (RIP-LCMV-GP) mice, while maintaining higher number of Treg cells throughout the antiviral response in the blood and spleen but not in the pancreatic lymph nodes. GP33-41-specific pentamer-positive cytotoxic lymphocytes (CTLs) are numerically reduced in the absence of Ptpn22 at the expansion and contraction phase but reach wild-type levels at the memory phase. However, they show similar effector function and even a subtle increase in the production of IL-2. In contrast, NP396-404-specific CTLs develop normally at all phases but display enhanced effector function. Lack of Ptpn22 also augments the memory proinflammatory response of GP61-80 CD4 T cells. Hence, lack of Ptpn22 largely augments antiviral effector T cell responses, suggesting that caution should be taken when targeting Ptpn22 to treat autoimmune diseases where viral infections are considered environmental triggers.
authors.affiliation: Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI) Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy. Electronic address: fousteri.georgia@hsr.it.
authors.forename: Georgia
authors.initials: G
authors.lastname: Fousteri
authors.affiliation: Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI) Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Jofra
authors.affiliation: Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI) Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Di Fonte
authors.affiliation: Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI) Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Mirela
authors.initials: M
authors.lastname: Kuka
authors.affiliation: Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI) Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Iannacone
authors.affiliation: Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI) Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Battaglia
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology* / Q000821:virology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D007156:Immunologic Memory; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010179:Pancreas / Q000276:immunology; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse
keywords: Cytotoxic lymphocytes (CTLs);; Memory CD8(+) T cells;; Ptpn22;; Treg cells; Type 1 diabetes (T1D);; Virally-induced T1D;