Background A single nucleotide polymorphism within the phosphatase PTPN22 increases the risk of developing multiple autoimmune and connective tissue diseases.1 Ptpn22 is a negative regulator of Syk and Src family kinases downstream of immuno-receptor signalling cascades.2 Fungal β-glucan receptor dectin-1, signals via Syk kinase, and induces dendritic cells to secrete pro-inflammatory cytokines IL-1β, IL-6, IL-12/23p40 and TNFα, in turn allowing the induction of IL-17 secreting T-cell responses, which are critical to the clearance of fungal infections.3 IL-17 has been implicated as a key cytokine in inflammatory responses associated with RA, JIA, and psoriasis.4
Objectives To investigate if Ptpn22 regulates dectin-1 signalling and controls the capability of dectin-1 matured BMDC to promote adaptive immune responses.
Methods GM-CSF bone marrow derived dendritic cells (BMDC) were generated from C57BL/6 WT, Ptpn22-/- or Ptpn22R619W (human PTPN22R620W orthologue) mice, and pulsed with OVA323–339 in the presence or absence of the dectin-1 agonist curdlan. Activated BMDC were co-cultured in vitro with OT-II T-cells or adoptively transferred into OT-II mice and the resulting T-cell response assessed. Cytokine secretion from curdlan activated Ptpn22 variant mouse BMDC was determined by immunoassay and the kinetics of Syk and Erk phosphorylation were determined by immunoblot.
Results We observed that Dectin-1 activated Ptpn22-/- BMDC had an enhanced capability to induce T-cell IL-17 secretion both in vitro and in vivo compared to WT BMDC. Following dectin-1 priming Ptpn22-/- BMDC secreted increased IL-1β compared to WT BMDC, and the increase in IL-1β was found to be sufficient to cause the enhanced IL-17 response induced by Ptpn22-/- BMDC. Dectin-1 induced IL-1β secretion was found to be Syk and Erk dependent and assessment of Syk and Erk kinetics of phosphorylation revealed that dectin-1 activated Ptpn22-/- BMDC displayed enhanced Syk and Erk phosphorylation compared to WT BMDC. Furthermore, Ptpn22R619W BMDC (orthologue of human Ptpn22R620W) exhibited a similar enhancement in IL-1β secretion and induced enhanced T-cell dependent IL-17 responses in vivo, indicating that the PTPN22 polymorphism behaves as a loss-of-function allele in the context of dectin-1 signals.
Conclusions Data highlight Ptpn22 as a novel regulator of dectin-1 signals and provide a link between genetically conferred perturbation to innate receptor signalling pathways and autoimmunity.
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Disclosure of Interest None declared
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