The protein tyrosine phosphatase PTPN22 controls forkhead box protein 3 T regulatory cell induction but is dispensable for T helper type 1 cell polarization.
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 PTPN22 encoding for a PTP that inhibits TCR signalling affects the generation of forkhead box protein 3 (FoxP3)(+) T regulatory (Treg ) cells and T helper type 1 (Th1) cells. Murine CD4(+) T cells isolated from Ptpn22 knock-out (Ptpn22(KO) ) mice cultured in Treg 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, Ptpn22(KO) CD4(+) 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(+) T cells into Treg cells. Notably, in vivo Treg cell conversion experiments in mice showed delayed kinetic but overall increased frequency and number of Treg cells in the absence of Ptpn22. In contrast, the in vitro and in vivo generation of Th1 cells was comparable between WT and Ptpn22(KO) 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(+) Treg cell differentiation.
['Fousteri|G|G|', 'Jofra|T|T|', 'Debernardis|I|I|', 'Stanford|S M|SM|', 'Laurenzi|A|A|', 'Bottini|N|N|', 'Battaglia|M|M|']
D000818:Animals D015496:CD4-Positive T-Lymphocytes D002454:Cell Differentiation D051858:Forkhead Transcription Factors D006801:Humans D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 D011948:Receptors, Antigen, T-Cell D050378:T-Lymphocytes, Regulatory D018417:Th1 Cells
PTPN22 Th1 cells FoxP3+ Treg cells