The tyrosine phosphatase PTPN22 discriminates weak self peptides from strong agonist TCR signals

Salmond, Robert J.; Brownlie, Rebecca J.; Morrison, Vicky L.; Zamoyska, Rose

doi:10.1038/ni.2958

Cited by 97 publications

(127 citation statements)

References 44 publications

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“…Normally, functional CD4 cells are required for clearance of LCMV. However, because PTPN22 deficiency has been reported to enhance CD8 function (27,31), it was of interest to determine whether PTPN22 −/− CD8 cells alone were capable of viral clearance. To determine whether CD4 T cells were necessary for the enhanced clearance of LCMV cl13 by PTPN22 −/− mice, we injected a group of mice with CD4-depleting antibody ( Fig.…”

Section: Ptpn22mentioning

confidence: 99%

“…Genome-wide association studies demonstrated the association of a minor allele of PTPN22 (R620W) with a number of autoimmune diseases including type I diabetes, rheumatoid arthritis, and systemic lupus erythematosus, among others (24)(25)(26). PTPN22-deficient mice have been instrumental in uncovering the role of this gene in T-cell function (27)(28)(29)(30)(31)(32). Aged mice develop splenomegaly and enlarged lymph nodes that exhibit the accumulation of effector/memory T cells, enlarged spontaneous germinal centers, and increased (non-autoreactive) serum IgG.…”

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confidence: 99%

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PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection

Maine

Teijaro

Marquardt

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The protein encoded by the autoimmune-associated protein tyrosine phosphatase nonreceptor type 22 gene, PTPN22, has wide-ranging effects in immune cells including suppression of T-cell receptor signaling and promoting efficient production of type I interferons (IFN-I) by myeloid cells. Here we show that mice deficient in PTPN22 resist chronic viral infection with lymphocytic choriomeningitis virus clone 13 (LCMV cl13). The numbers and function of viral-specific CD4 T lymphocytes is greatly enhanced, whereas expression of the IFNβ-induced IL-2 repressor, cAMP-responsive element modulator (CREM) is reduced. Reduction of CREM expression in wild-type CD4 T lymphocytes prevents the loss of IL-2 production by CD4 T lymphocytes during infection with LCMV cl13. These findings implicate the IFNβ/CREM/IL-2 axis in regulating T-lymphocyte function during chronic viral infection.

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Section: Ptpn22mentioning

confidence: 99%

mentioning

confidence: 99%

PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection

Maine

Teijaro

Marquardt

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The kinetics of OT-I T cells in response to OVA257-264 stimulation was similar to previously published findings (Salmond et al, 2014), although the peptide concentration required for maximal T-cell activation was lower in the present study. This could be due to different stimulation periods, 18 hours in the present study compared to 4 hours in the study by Salmond et al Overall, the outcomes of the peptide titration studies confirmed G9 T cells exhibit a low affinity for their cognate determinant from insulin.…”

Section: Discussionsupporting

confidence: 79%

Transgenic expression of proinsulin to inactivate insulin-specific CD8+ T-cell responses in autoimmune diabetes

Reeves¹

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Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic β cells. The current treatment for the fatal insulin-deficiency in T1D is injection of exogenous insulin. Despite the dramatic increase in survival from the use of exogenous insulin, complications develop from imperfect glycemic control and exogenous insulin does not rectify the underlying cause of disease, the diabetogenic autoimmune response. Hence, there is a need for an effective therapy that impedes the progress of the pathogenic autoimmune response. β cell-reactive CD8 + In the NOD mouse model of T1D, insulin is the primary β-cell antigen that elicits disease. As such, I have investigated T-cell tolerance to insulin in an adoptive transfer setting in which TCR transgenic (G9) CD8 + T cells specific for insulin B15-23 (InsB15-23) were transferred to transgenic mice over-expressing proinsulin in APC. Subsequently, I examined the effect of introducing transgenic proinsulin expression on diabetes development in wild type NOD mice.When transferred to mice transgenically expressing proinsulin, naïve G9 T cells proliferated extensively prior to undergoing rapid deletion. In proinsulin transgenic recipients, the remaining population of G9 T cells displayed reduced T-cell receptor (TCR) expression and bound less InsB15-23-loaded, H2-K d -tetramer compared to G9 T cells that had been transferred to non-transgenic NOD recipients. Interestingly, TCR down-regulation represented that which occurred for OVA-specific CD8 + T cells transferred to mice expressing OVA in APC in a non-autoimmune prone strain.Importantly, naïve G9 T cells did not expand or produce the important effector cytokine, interferon (IFN)-γ, in response to InsB15-23 immunisation after transfer to proinsulin transgenic mice. These data confirm naïve G9 T cells undergo rapid deletion and inactivation after transfer to mice transgenically-expressing proinsulin, despite genetic tolerance defects in NOD mice. Memory CD8 + T cells (Tmem) perpetuate β-cell autoimmunity and pose a distinct barrier to immunotherapy. It was pertinent to determine whether inactivation of insulin-specific CD8 + Tmem also occurs after transfer to mice expressing proinsulin in APC. To test inactivation of insulin-specific CD8 + Tmem, G9 Tmem were generated using an in vitro culture method. Cultured G9 Tmem were validated by assessing phenotypic markers and cytokine production. Similarly to naïve G9 T cells, G9 Tmem proliferated extensively and most G9 Tmem were rapidly deleted after transfer to mice overexpressing proinsulin in APC. The remaining, non-deleted population of G9 Tmem was infrequent ii and exhibited reduced TCR expression. Furthermore, G9 Tmem did not expand or produce IFN-γ in response to InsB15-23 immunisation, consistent with functional inactivation. These results demonstrate transgenic proinsulin expression in APC overcomes genetic defects in NOD mice to induce tolerance in insulin-specific CD8 + Tmem.From the data described above, transgenic proinsulin expression is tolerogenic for in...

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“…After 7 days, the frequency and number of P14.PTPN22 − / − donor T cells recovered was significantly higher (Figure 4b), a finding that is consistent with a previous report using OT-I TCR Tg mice. 14 The central memory-like phenotype of the expanded cells was also higher on PTPN22-deficient P14 cells (Figure 4c). Interestingly, expression levels of LFA-1 and FAS were similar to that observed in LCMV-infection experiments, that is, higher expression levels on P14.PTPN22 − / − T cells (Figures 4e and f).…”

Section: Ptpn22-deficient P14 T Cells Show Enhanced Homeostatic Prolimentioning

confidence: 91%

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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The tyrosine phosphatase PTPN22 discriminates weak self peptides from strong agonist TCR signals

Cited by 97 publications

References 44 publications

PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection

PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection

Transgenic expression of proinsulin to inactivate insulin-specific CD8+ T-cell responses in autoimmune diabetes

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

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