PTPN2 attenuates T-cell lymphopenia-induced proliferation

Abstract

When the peripheral T-cell pool is depleted, T cells undergo homoeostatic expansion. This expansion is reliant on the recognition of self-antigens and/or cytokines, in particular interleukin-7. The T cell-intrinsic mechanisms that prevent excessive homoeostatic T-cell responses and consequent overt autoreactivity remain poorly defined. Here we show that protein tyrosine phosphatase N2 (PTPN2) is elevated in naive T cells leaving the thymus to restrict homoeostatic T-cell proliferation and prevent excess responses to self-antigens in the periphery. PTPN2-deficient CD8 þ T cells undergo rapid lymphopenia-induced proliferation (LIP) when transferred into lymphopenic hosts and acquire the characteristics of antigenexperienced effector T cells. The enhanced LIP is attributed to elevated T-cell receptordependent, but not interleukin-7-dependent responses, results in a skewed T-cell receptor repertoire and the development of autoimmunity. Our results identify a major mechanism by which homoeostatic T-cell responses are tuned to prevent the development of autoimmune and inflammatory disorders.

miR-155 augments CD8 + T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γ c cytokines

“…4D). Ptpn2 is a negative regulator of Jak3/Stat5 signaling that has been shown to restrain homoeostatic T-cell responses (29). Furthermore, knockdown of PTPN2 in human T-cell acute lymphoblastic leukemia increased the proliferation and cytokine sensitivity of leukemic cells (30), a phenotype closely resembling the effects of miR-155 overexpression in our model.…”

Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling

“…Although the hurdle of developing of selective PTP1B and TCPTP inhibitors has been demonstrably overcome, a significant albeit not insurmountable challenge remains in selectively targeting the brain. This is particularly important for TCPTP given its role in hematopoietic development and autoimmunity [112][113][114][115]. Although TCPTP heterozygous deficiency does not result in any overt immune phenotype [112], TCPTP heterozygoisty is sufficient to enhance T cell responses to self-antigen and autoimmunity, with age [115], in the context of lymphopenia [113] and in a mouse model of type 1 diabetes [114].…”

“…This is particularly important for TCPTP given its role in hematopoietic development and autoimmunity [112][113][114][115]. Although TCPTP heterozygous deficiency does not result in any overt immune phenotype [112], TCPTP heterozygoisty is sufficient to enhance T cell responses to self-antigen and autoimmunity, with age [115], in the context of lymphopenia [113] and in a mouse model of type 1 diabetes [114]. Despite this, recent work aimed at improving wholebody insulin sensitivity through the intranasal application of insulin and the enhancement of hypothalamic and parasympathetic outputs in humans [47,48,74,116], suggests that selective CNS delivery of PTP1B/TCPTP inhibitors might be a viable option.…”

Deficiency of Protein Tyrosine Phosphatase Non-Receptor Type 2 in Intestinal Epithelial Cells Has No Appreciable Impact on Dextran Sulphate Sodium Colitis Severity But Promotes Wound Healing

“…When PTPN2 function is lost in IECs, the body seems to be able to compensate this shortcoming. However, in vivo studies using other tissue-specific PTPN2 knock out mouse strains have already demonstrated the importance of this phosphatase for the development of CD4 + cells [28] but also for TCR signalling and lymphopenia-induced proliferation in CD8 + cells [29,30] . Apparently, loss of PTPN2 in the T cell compartment cannot be counterbalanced and leads to strong phenotypes.…”