The role of PTPN2 in early thymocyte development and JAK/STAT signaling (#351)
The role of common -chain receptor cytokines in the promotion of thymocyte development and peripheral T cell survival is well characterized. However, the mechanisms by which cytokine signaling is attenuated during T cell development, particularly at the double-negative (DN) stages, remain unclear. We have shown previously that the protein tyrosine phosphatase PTPN2 acts as a key negative regulator in T cells and contributes to central tolerance and the prevention of excessive responses to self-antigen in the periphery.1,2 The Janus kinases (JAK) 1 and 2 and the transcription factors STAT1, STAT3 and STAT5 are bona fide substrates of PTPN2.
Our studies indicate that global PTPN2 deficiency in mice enhances STAT5 signaling during early thymocyte development. DN thymocytes isolated from Ptpn2–/– mice exhibited increased STAT5 phosphorylation at DN stages 2 and 3 resulting in elevated Bcl-2 levels and enhanced thymocyte survival. Studies with mixed bone marrow chimeras demonstrated that PTPN2-deficient thymocytes outcompeted their wild type counterparts in lethally irradiated congenic wild type hosts at DN stages 3 and 4. In addition, T cell progenitors isolated from the bone marrow of Ptpn2–/– mice transitioned faster through the DN-stages when compared to wild type control cells using the OP9-DL1 system ex vivo. In contrast, retrovirally transduced over-expression of PTPN2 in bone-marrow chimeras prevented progression beyond DN stage 2.
These results indicate that PTPN2 is required to restrain thymocyte selection at the DN stages in a cell-intrinsic manner through the inhibition of the JAK/STAT5 pathway. These findings are consistent with studies showing that Interleukin-7 (IL-7)-induced STAT5 signaling is crucial for T cell development and survival and the progression of DN thymocytes to the double-positive (DP) stage. Our results identify PTPN2 as a critical regulatory element in early T cell development.
- Wiede et al. J Clin Invest. 2011 December 1; 121(12): 4758–4774.
- Wiede et al. Nat.Commun. 2014 January; 5:3073.