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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. ? 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. IFN? production) and reduced Th17 responses (e.g. IL-17 production). Importantly, while regulatory T cells normally suppressed Th1-mediated IFN? 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.

SUBMITTER: Vang T 

PROVIDER: S-EPMC4011173 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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The autoimmune-predisposing variant of lymphoid tyrosine phosphatase favors T helper 1 responses.

Vang Torkel T   Landskron Johannes J   Viken Marte K MK   Oberprieler Nikolaus N   Torgersen Knut M KM   Mustelin Tomas T   Tasken Kjetil K   Tautz Lutz L   Rickert Robert C RC   Lie Benedicte A BA  

Human immunology 20130117 5


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 f  ...[more]

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