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

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. zeta chain phosphorylation) but augmented CD28-associated signaling (e.g. ART 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 gamma production) and reduced Th17 responses (e.g. IL-17 production). Importantly, while regulatory T cells normally suppressed Th1 -mediated IFN gamma 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. (C) 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.