T-cell protein tyrosine phosphatase deletion results in progressive systemic inflammatory disease

Abstract

The deregulation of the immune response is a critical component in inflammatory disease. Recent in vitro data show that T-cell protein tyrosine phosphatase (TC-PTP) is a negative regulator of cytokine signaling. Furthermore, tc-ptp ؊/؊ mice display immune defects and die within 5 weeks of birth. We report here that tcptp ؊/؊ mice develop progressive systemic inflammatory disease as shown by chronic myocarditis, gastritis, nephritis, and sialadenitis as well as elevated serum interferon-␥. The widespread mononuclear cellular infiltrates correlate with exaggerated interferon-␥, tumor necrosis factor-␣, interleukin-12, and nitric oxide production in vivo. Macrophages grown from tc-ptp ؊/؊ mice are inherently hypersensitive to lipopolysaccharide, which can also be detected in vivo as an increased susceptibility to endotoxic shock. These results identify T-cell protein tyrosine phosphatase as a key modulator of inflammatory signals and macrophage function. ( IntroductionProtein phosphorylation, the most common posttranslational modification in mammalian cells, is used as a rapid means of modulating enzyme function. The control of cellular phosphorylation levels depends on the reciprocal activity of kinases and phosphatases, and defects in either component can have widespread effects on cell function. T-cell protein tyrosine phosphatase (TC-PTP) is a nuclear phosphatase that is strongly expressed in the hematopoietic system. We have previously shown that it is essential for coordinate immune function and development. 1 More recently, it has been identified as a negative regulator of signal transduction associated with cytokine signaling through Janus kinases 1 (JAK-1) and -3 2 as well as several members of the signal transducers and activators of transcription (STAT) family. [3][4][5] The tc-ptp Ϫ/Ϫ mice show normal genotypic frequency at birth and appear to be physically normal until 10 to 14 days of age, after which their growth is retarded. 1,6 Although the total number of peripheral T and B cells remains relatively unchanged, the tc-ptp Ϫ/Ϫ mice are severely immunosuppressed. They are unable to mount T-cell-dependent B-cell responses, 1 and their splenocyte response to mitogens is totally suppressed. Moreover, thymic double-positive T cells decline sharply with age, and stromal defects in the bone marrow result in depletion of B-cell precursors by 3 weeks of age. 1 The tc-ptp Ϫ/Ϫ mice progressively develop symptoms of wasting disease, 7-9 including runting, hunched posture, diarrhea, and weight loss 1 and die at 3 to 5 weeks of age.Severe immune suppression accompanied by wasting disease is a hallmark of graft-versus-host disease (GVHD), which is characterized by a loss of T-cell proliferative responses and the systemic priming of macrophages. [10][11][12][13] Unstimulated macrophages from normal animals respond to an interferon-␥ (IFN-␥) plus lipopolysaccharide (LPS) activation by producing tumor necrosis factor-␣ (TNF-␣) 14,15 and nitric oxide (NO). 16,17 Both are mediators of tissue damage [7][8][9]18,19 that ...

T cell protein tyrosine phosphatase deficiency results in spontaneous synovitis and subchondral bone resorption in mice

“…While our group has previously described increased macrophage numbers and sensitivity in TC-PTP Ϫ/Ϫ mice (4,15), the increase in FLS was unexpected. Since we did not observe a significant increase in the cellularity of the synovial lining, the increase in FLS, detected by flow cytometry based on VCAM-1 and CD90.2 expression, may be due to up-regulation of these surface markers in response to the surrounding inflammatory environment.…”

“…Mice deficient in TC-PTP die within 5 weeks after birth (2) and have defective hematopoiesis (3,4), anemia, and severe systemic progressive inflammation characterized by the infiltration of mononuclear cells in several tissues and high levels of various proinflammatory cytokines, including tumor necrosis factor ␣ (TNF␣) (5). TNF␣ plays a central role in the pathogenesis of rheumatoid arthritis (RA), as indicated in experimental models in which mice overexpressing transgenic TNF␣ develop spontaneous arthritis (6,7).…”

Spermidine Stimulates T Cell Protein-tyrosine Phosphatase-mediated Protection of Intestinal Epithelial Barrier Function

“…This view is supported by the fact that Ptpn2 knockout mice die within 3-5 weeks from systemic inflammation characterized by elevated levels of IFN-␥ and TNF-␣ (22). Single nucleotide polymorphisms (SNPs) in the PTPN2 gene locus that encodes TCPTP have been associated with inflammatory bowel disease, and it is thought that these mutations could lead to a loss of function (10,11).…”

TC-PTP–deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-γ

“…TC-PTP Ϫ/Ϫ mice appear physically normal until 10 to 14 days of age, at which time they progressively develop tissue mononuclear cell infiltrates. 2 Elevated levels of IFN-␥ can be measured at 19 days of age, 3 and the animals die between 21 and 35 days of age. TC-PTP Ϫ/Ϫ mice display defective hematopoiesis and immune function, characterized by anemia and splenomegaly secondary to sequestration of erythrocytes and accumulation of myeloid cells.…”