Abstract
A C1858T single nucleotide polymorphism within PTPN22 (which encodes PTPN22R620W) is associated with an enhanced susceptibility to multiple autoimmune diseases including type 1 diabetes and rheumatoid arthritis. Many of the associated autoimmune diseases have an autoantibody component to their pathology. Fc receptors (FcRs) recognise autoantibodies when they bind to autoantigens and form immune complexes. After immune complex binding and receptor crosslinking, FcRs signal via Src and Syk family kinases, leading to antigen uptake, presentation and cytokine secretion. Ptpn22 encodes a protein tyrosine phosphatase that negatively regulates Src and Syk family kinases proximal to immunoreceptor signalling cascades. We therefore hypothesised that PTPN22 regulates immune complex stimulated FcR responses in dendritic cells (DCs). Bone marrow derived DCs (BMDCs) from wild type (WT) or Ptpn22−/− mice were pulsed with ovalbumin:anti-ovalbumin immune complexes (ova ICs). Co-culture with WT OT-II T cells revealed that ova IC pulsed Ptpn22−/− BMDCs have an enhanced capability to induce T cell proliferation. This was associated with an increased capability of Ptpn22−/− BMDCs to present immune complex derived antigens and to form ova IC dependent DC-T cell conjugates. These findings highlight PTPN22 as a regulator of FcR mediated responses and provide a link between the association of PTPN22R620W with autoantibody associated autoimmune diseases.
Highlights
The C1858T single nucleotide polymorphism in the human protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene encodes an R620W missense mutation in PTPN22 and is associated with an increased susceptibility to multiple autoimmune diseases including rheumatoid arthritis (RA)[1,2,3,4], systemic lupus erythematosus (SLE)[5,6] and type 1 diabetes (T1D)[7,8,9]
Wild type (WT) and Ptpn22−/− Bone marrow derived DCs (BMDCs) were pulsed with ovalbumin and ova immune complexes (ICs) and co-cultured with ova specific WT CD4+ OT-II T cells
We have previously shown that ova and ova[323–339] peptide pulsed WT and Ptpn22−/− BMDCs induce comparable WT CD4+ OT-II T cell proliferation[30]
Summary
The C1858T single nucleotide polymorphism in the human protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene encodes an R620W missense mutation in PTPN22 and is associated with an increased susceptibility to multiple autoimmune diseases including rheumatoid arthritis (RA)[1,2,3,4], systemic lupus erythematosus (SLE)[5,6] and type 1 diabetes (T1D)[7,8,9]. PTPN22 ( known as PEP in the mouse) was first described as a negative regulator of Src and Syk family kinases downstream of the T cell receptor (TCR). In keeping with this function, Ptpn22−/− mice were subsequently reported to display enhanced TCR signalling that results in expansion of CD4+ effector T cells[10]. Given the link between PTPN22R620W and autoantibody associated autoimmune diseases, and the regulation of FcRs by Src and Syk family kinases, we set out to investigate if PTPN22 regulates FcγR dependent immune complex uptake and activation in DCs and whether this can alter T cell effector responses
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