Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling

Holmes, Derek A; Suto, Eric; Lee, Wyne P.; Ou, Qinglin; Gong, Qian; Smith, Hamish R.C.; Caplazi, Patrick; Chan, Andrew C.

doi:10.1084/jem.20142130

Cited by 23 publications

(25 citation statements)

References 64 publications

(115 reference statements)

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“…PTPN22 's effect on the risk of autoimmunity was initially ascribed to this gene's role in antigen receptor signaling (17–20). However, subsequent studies have shown that PTPN22 participates in a diverse array of signaling pathways, including Toll-like receptor and IFN-α receptor signaling (21, 22). The exact cause for PTPN22 's association with type 1 diabetes and other autoimmune diseases thus remains elusive.…”

Section: Discussionmentioning

confidence: 99%

Ptpn22 Modifies Regulatory T Cell Homeostasis via GITR Upregulation

Nowakowska

Kissler

2016

The Journal of Immunology

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PTPN22 gene variation associates with multiple autoimmune diseases including type 1 diabetes and rheumatoid arthritis. Loss of function studies have demonstrated that PTPN22 impinges on the homeostatic behavior of regulatory T (Treg) cells, a lineage critical for immune tolerance. The frequency and absolute number of Treg cells is increased in Ptpn22 deficient mice, but the mechanism driving this increase is unknown. We show here that Ptpn22 knockdown (KD) promoted the expansion of the Treg cell compartment by up-regulating the glucocorticoid-induced TNF receptor family-related protein (GITR) and increasing GITR signaling. Ptpn22 KD did not accelerate cell division but instead prolonged Treg cell survival, as measured by a decrease in the frequency of apoptotic Treg cells. Loss of Ptpn22 caused a concomitant increase in the proportion of CD44hiCD62Llo ‘effector’ Treg cells, at the expense of CD44loCD62Lhi ‘central’ Treg cells. The increase in Treg cell numbers, but not their differentiation towards an effector phenotype, was dependent on GITR signaling, because blockade of GITR-L prevented Treg cell expansion caused by Ptpn22 KD. These findings indicate that GITR plays a key role in regulating the overall size of the Treg cell pool. Our results suggest that the size and composition of the Treg cell compartment are independently controlled, and have implications for the design of immunotherapies that seek to improve Treg cell function.

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Section: Discussionmentioning

confidence: 99%

Ptpn22 Modifies Regulatory T Cell Homeostasis via GITR Upregulation

Nowakowska

Kissler

2016

The Journal of Immunology

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“…Further complicating matters include the fact that PTPN22 − / − hematopoietic progenitors demonstrate increased IFNAR signaling and enhanced proliferation and activation compared with PTPN22+/+ progenitors in response to IFN-α. 16 Our study provides novel insights by which loss-of-function PTPN22 alleles possibly lead to autoimmunity. They act by augmenting the expansion of low-affinity autoreactive CD8 T cells responding to homeostatic signals rather than to inflammatory signals triggered by acute infections.…”

Section: Ptpn22 Positively Regulates Type I Interferon Signaling In Tmentioning

confidence: 86%

Protein tyrosine phosphatase PTPN22 has dual roles in promoting pathogen versus homeostatic‐driven CD8 T‐cell responses

et al. 2016

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PTPN22 (protein tyrosine phosphatase non receptor 22) encodes a tyrosine phosphatase that functions as a key regulator of immune homeostasis. In particular, PTPN22 inhibits T-cell receptor signaling and selectively promotes type I interferon responses in myeloid cells. To date, there is little information on the CD8 T-cell-intrinsic role of PTPN22 in response to a viral pathogen. We unexpectedly found that PTPN22-deficient virus-specific CD8 T cells failed to accumulate in wild-type hosts after lymphocytic choriomeningitis virus infection. Lack of PTPN22 expression altered CD8 T-cell activation and antiviral cytokine production, but did not significantly affect the composition of effector and memory cell precursors. Most significantly, in vivo, PTPN22-deficient CD8 T cells showed a profound defect in upregulating STAT-1 after lymphocytic choriomeningitis virus infection and considerably less phosphorylation of STAT-1 in response to IFN-α treatment in vitro compared with their wild-type counterparts. In stark contrast, following transfer into lymphopenic mice, CD8 T-cell expansion and central-like phenotype, was considerably increased in the absence of PTPN22. Collectively, our results suggest that PTPN22 has dual roles in T-cell clonal expansion and effector function; whereas it promotes antigen-driven responses during acute infection by positively regulating interferon signaling in T cells, PTPN22 inhibits homeostatic-driven proliferation. The protein tyrosine phosphatase non receptor 22 (PTPN22) has attracted a lot of attention due to its association with various autoimmune diseases including type 1 diabetes and rheumatoid arthritis. 1 To date, it remains poorly understood how PTPN22 influences the balance between tolerance and immunity, which may lead in understanding how it predisposes to autoimmunity. 2 Much of our knowledge regarding the role of PTPN22 in immune regulation derives from studies in PTPN22-deficient or PTPN22 single-nucleotide-polymorphism-knock-in mice. Both reported an accumulation of hyper-responsive T cells with effector-memory phenotype, a result which suggested that, at least in mice, the single-nucleotide polymorphism acts as a loss-of-function allele. [3][4][5] Thus, most studies conducted with murine lymphocytes so far pinpoint PTPN22 as a negative regulator of T-cell receptor (TCR) signaling.A recent key finding showed that PTPN22 controls innate immune mechanisms by potentiating Toll-like receptor-driven type 1 interferon-dependent immunity. 6 Innate immunity has direct effect on T cells and consequently, PTPN22 − / − mice showed impaired expansion of virus-specific cytotoxic T lymphocytes (CTLs) after infection with lymphocytic choriomeningitis virus (LCMV). 6,7 The role of PTPN22 in T cells in vivo in the LCMV experimental setting, however, was analyzed in a model in which a direct effect of PTPN22 was difficult to distinguish from indirect effects mediated by the innate immunity. Therefore, it was not possible to determine whether the reduced expansion of LCMV-specific CTLs was ...

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“…For example, in myeloid cells, rather than act as a negative regulator, PTPN22 enhances production of type 1 interferons (IFNs) . Conversely, PTPN22 negatively regulates type 1 IFN‐receptor signalling pathways . A clear example of cell‐extrinsic effects of PTPN22 on T‐cell function comes from studies of chronic viral infection.…”

Section: Non‐cell Intrinsic Effects Of Ptpn22 On T‐cellsmentioning

confidence: 99%

Regulation of autoimmune and anti‐tumour T‐cell responses by PTPN22

2018

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A number of polymorphisms in immune-regulatory genes have been identified as risk factors for the development of autoimmune disease. PTPN22 (that encodes a tyrosine phosphatase) has been associated with the development of several autoimmune diseases, including type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus. PTPN22 regulates the activity and effector functions of multiple important immune cell types, including lymphocytes, granulocytes and myeloid cells. In this review, we describe the role of PTPN22 in regulating T-cell activation and effector responses. We discuss progress in our understanding of the impact of PTPN22 in autoimmune disease in humans and mouse models, as well as recent evidence suggesting that genetic manipulation of PTPN22 expression might enhance the efficacy of anti-tumour T-cell responses.

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Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling

Cited by 23 publications

References 64 publications

Ptpn22 Modifies Regulatory T Cell Homeostasis via GITR Upregulation

Ptpn22 Modifies Regulatory T Cell Homeostasis via GITR Upregulation

Protein tyrosine phosphatase PTPN22 has dual roles in promoting pathogen versus homeostatic‐driven CD8 T‐cell responses

Regulation of autoimmune and anti‐tumour T‐cell responses by PTPN22

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