title: Reduced CD4+T cell activation in children with type 1 diabetes carrying the PTPN22/Lyp 620Trp variant.
abstract: The 620Trp variant of the LYP protein, encoded by the lymphoid tyrosine phosphatase 22 gene (PTPN22), is associated with autoimmunity. In this study we aimed at characterising the role of this variant on lymphocyte activation. We analysed cytokine secretion and proliferation of peripheral blood mononuclear cells (PBMCs) and CD4(+)T cells in a cohort of clinically non-diabetic, multiple autoantibody-positive children, healthy controls and in children with type 1 diabetes (T1D). We found a decreased proliferation and IL-2 production of CD4(+)T cells after anti-CD3/anti-CD28 stimulation (p=0.04 for IL-2) among T1D patients. In addition, a profoundly decreased intracellular calcium flux in CD4(+)T cells after PHA stimulus was detected among 620Trp carriers. In contrast, no effect of this polymorphism on tuberculin and tetanus toxoid induced PBMC proliferation and cytokine secretion was observed in autoantibody positive children, healthy controls and children with newly-diagnosed T1D. In conclusion, the LYP 620Trp variant is associated with reduced activation, proliferation and IL-2 production in CD4(+)T cells among T1D patients. In accordance with our previous findings on the key role of this variant on disease progression, this mechanism is likely to contribute to the development of beta-cell specific autoimmunity.
authors.affiliation: Immunogenetics Laboratory, University of Turku, MediCity Research Laboratories, BioCity 4th Floor, Tykistökatu 6A, 20520 Turku, Finland. johanna.aarnisalo@utu.fi
authors.forename: Johanna
authors.initials: J
authors.lastname: Aarnisalo
authors.forename: Andras
authors.initials: A
authors.lastname: Treszl
authors.forename: Peter
authors.initials: P
authors.lastname: Svec
authors.forename: Jane
authors.initials: J
authors.lastname: Marttila
authors.forename: Viveka
authors.initials: V
authors.lastname: Oling
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.forename: Anna
authors.initials: A
authors.lastname: Körner
authors.forename: Laszlo
authors.initials: L
authors.lastname: Madacsy
authors.forename: Barna
authors.initials: B
authors.lastname: Vasarhelyi
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.forename: Robert
authors.initials: R
authors.lastname: Hermann
mesh_terms: D000293:Adolescent; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D008297:Male; D011110:Polymorphism, Genetic; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000276:immunology*
chemical_list: D007376:Interleukin-2; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22