title: The autoimmune-predisposing variant of lymphoid tyrosine phosphatase favors T helper 1 responses.
abstract: The C1858T single nucleotide polymorphism in PTPN22, which is the gene encoding lymphoid tyrosine phosphatase (LYP), confers increased risk for various autoimmune disorders in Caucasians. Although the disease-associated LYP allele (LYP*W620) is a gain-of-function variant that has higher catalytic activity than the major allele (LYP*R620), it is still unclear how LYP*W620 predisposes for autoimmunity. Here, we compared both T cell signaling and T cell function in healthy human donors homozygous for either LYP*R620 or LYP*W620. Generally, the presence of LYP*W620 caused reduced proximal T cell antigen receptor-mediated signaling (e.g. ζ chain phosphorylation) but augmented CD28-associated signaling (e.g. AKT activation). Altered ligand binding properties of the two LYP variants could explain these findings since LYP*R620 interacted more strongly with the p85 subunit of PI3K. Variation in signaling between cells expressing either LYP*R620 or LYP*W620 also affected the differentiation of conventional CD4(+) T cells. For example, LYP*W620 homozygous donors displayed exaggerated Th1 responses (e.g. IFNγ production) and reduced Th17 responses (e.g. IL-17 production). Importantly, while regulatory T cells normally suppressed Th1-mediated IFNγ production in LYP*R620 homozygous individuals, such suppression was lost in LYP*W620 homozygous individuals. Altogether, these findings provide a molecular and cellular explanation for the autoimmune phenotype associated with LYP*W620.
authors: Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway. torkelvan@yahoo.com
authors: Torkel
authors: T
authors: Vang
authors: Johannes
authors: J
authors: Landskron
authors: Marte K
authors: MK
authors: Viken
authors: Nikolaus
authors: N
authors: Oberprieler
authors: Knut M
authors: KM
authors: Torgersen
authors: Tomas
authors: T
authors: Mustelin
authors: Kjetil
authors: K
authors: Tasken
authors: Lutz
authors: L
authors: Tautz
authors: Robert C
authors: RC
authors: Rickert
authors: Benedicte A
authors: BA
authors: Lie
mesh_terms: D000328:Adult; D000483:Alleles; D001327:Autoimmune Diseases / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22