The protein tyrosine phosphatase PTPN22 controls forkhead box protein 3 T regulatory cell induction but is dispensable for T helper type 1 cell polarization. (October 2014)

• Record Type: Journal Article
• Authors: Fousteri, G.; Jofra, T.; Debernardis, I.; Stanford, S. M.; Laurenzi, A.; Bottini, N.; Battaglia, M.
• Is Part Of: Clinical and experimental immunology. Volume 178:Number 1(2014:Oct.)
• Page Start: 178
• Page End: 189
• Publication Date: 2014-10
• Subjects: Immunopathology -- Periodicals; 616.079
• DOI: 10.1111/cei.12393
• Languages: English
• ISSNs: 0009-9104

Abstract

<abstract abstract-type="main"> <title>Summary</title> <p>Protein tyrosine phosphatases (PTPs) regulate T cell receptor (TCR) signalling and thus have a role in T cell differentiation. Here we tested whether the autoimmune predisposing gene <italic>PTPN22</italic> encoding for a PTP that inhibits TCR signalling affects the generation of forkhead box protein 3 (FoxP3)<sup>+</sup> T regulatory (T<sub>reg</sub>) cells and T helper type 1 (Th1) cells. Murine CD4<sup>+</sup> T cells isolated from <italic>Ptpn22</italic> knock‐out (<italic>Ptpn22</italic><sup>KO</sup>) mice cultured in T<sub>reg</sub> cell polarizing conditions showed increased sensitivity to TCR activation compared to wild‐type (WT) cells, and subsequently reduced FoxP3 expression at optimal‐to‐high levels of activation. However, at lower levels of TCR activation, <italic>Ptpn22</italic><sup>KO</sup> CD4<sup>+</sup> T cells showed enhanced expression of FoxP3. Similar experiments in humans revealed that at optimal levels of TCR activation PTPN22 knock‐down by specific oligonucleotides compromises the differentiation of naive CD4<sup>+</sup> T cells into T<sub>reg</sub> cells. Notably, <italic>in vivo</italic> T<sub>reg</sub> cell conversion experiments in mice showed delayed kinetic but overall increased frequency and number of T<sub>reg</sub> cells in the absence of Ptpn<italic>22</italic>. In contrast, the <italic>in vitro</italic> and <italic>in vivo</italic> generation of Th1 cells was comparable between WT and <italic>Ptpn22</italic><sup>KO</sup> mice, thus suggesting PTPN22 as a FoxP3‐specific regulating factor. Together, these results propose PTPN22 as a key factor in setting the proper threshold for FoxP3<sup>+</sup> T<sub>reg</sub> cell differentiation.</p> </abstract>