PTPN2 controls differentiation of CD4+ T cells and limits intestinal inflammation and intestinal dysbiosis

Abstract

Loss-of-function variants within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with increased risk for Crohn's disease (CD). A disturbed regulation of T helper (Th) cell responses causing loss of tolerance against self- or commensal-derived antigens and an altered intestinal microbiota plays a pivotal role in CD pathogenesis. Loss of PTPN2 in the T-cell compartment causes enhanced induction of Th1 and Th17 cells, but impaired induction of regulatory T cells (Tregs) in several mouse colitis models, namely acute and chronic dextran sodium sulfate colitis, and T-cell transfer colitis models. This results in increased susceptibility to intestinal inflammation and intestinal dysbiosis which is comparable with that observed in CD patients. We detected inflammatory infiltrates in liver, kidney, and skin and elevated autoantibody levels indicating systemic loss of tolerance in PTPN2-deficient animals. CD patients featuring a loss-of-function PTPN2 variant exhibit enhanced Th1 and Th17 cell, but reduced Treg markers when compared with PTPN2 wild-type patients in serum and intestinal tissue samples. Our data demonstrate that dysfunction of PTPN2 results in aberrant T-cell differentiation and intestinal dysbiosis similar to those observed in human CD. Our findings indicate a novel and crucial role for PTPN2 in chronic intestinal inflammation.

Overexpression of PTPN2 in Visceral Adipose Tissue Ameliorated Atherosclerosis via T Cells Polarization Shift in Diabetic Apoe-/- Mice

“…Spalinger et al reported that loss of PTPN2 in the T-cell compartment caused enhanced induction of Th1 and Th17 cells, but impaired induction of Treg in several mouse colitis models [22]. We found the expression of PTPN2 was significantly decreased in diabetic EWAT.…”

“…PTPN2 might be the key regulator that controls the T cells polarization [22, 23]. Spalinger et al reported that loss of PTPN2 in the T-cell compartment caused enhanced induction of Th1 and Th17 cells, but impaired induction of Treg in several mouse colitis models [22].…”

“…It is ubiquitously expressed (e.g., intestinal and renal epithelium, fibroblasts, hepatocytes), but an extraordinary high expression is observed in lymphoid cells, including T cells [25]. Loss of PTPN2 in the T cell compartment causes enhanced induction of Th1 and Th17 cells, but impaired induction of Treg in several mouse colitis models [22]. However, the role of PTPN2 in adipose tissue T cells polarization remains unknown.…”

“…Protein tyrosine phosphatase non-receptor type 2 (PTPN2, gene ID: 19255) might be the key regulator that controls the T cells polarization [22, 23]. PTPN2, one of 17 intracellular and non-receptor PTPs, was originally cloned from a human T-cell cDNA library [24].…”

“…Accumulating evidence implicates T cells are important modulators of ATMs polarization and play an important role in the initiation and perpetuation of adipose tissue inflammation [13, 15, 16]. Pro-inflammatory T-helper 1 (Th1) and T-helper 17 (Th17) lymphocytes infiltrate VAT, where they overcome the anti-inflammatory effects of T-regulatory (Treg) cells, promoting classical activation of macrophages and systemic insulin resistance or glucose intolerance [14, 17-22]. The key signaling mediators that regulate T cells polarization during diabetes, however, are largely unexplored.…”