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

Abstract

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 ...

Extrinsic Protein Tyrosine Phosphatase Non-Receptor 22 Signals Contribute to CD8 T Cell Exhaustion and Promote Persistence of Chronic Lymphocytic Choriomeningitis Virus Infection

“…By utilizing the TCR transgenic system specific for the LCMV immunodominant epitope GP 33–41 (P14) and adoptive transfer experiments, we previously showed that P14.PTPN22 −/− CD8 T cells fail to expand in PTPN22-sufficient hosts following infection with the acute viral strain of LCMV (Arm) due to T cell-intrinsic defects in IFNAR signaling (12). Here, we show that PTPN22 promotes CTL exhaustion in the LCMV Cl13 system via T cell-extrinsic factors.…”

“…Recent studies addressing the role of Ptpn22 in antiviral immunity either by studying PTPN22 −/− mice or cells from carriers of the autoimmune-associated variant showed a clear link between PTPN22 and effective responses to acute viral infection (9). In the setting of acute lymphocytic choriomeningitis virus Armstrong (LCMV Arm) infection, it has been shown that mice deficient for PTPN22 produce reduced number of LCMV-specific cytotoxic lymphocytes (CTLs) due to a weakened innate immune response and T cell-intrinsic defects in response to type I IFNs (10–12). However, pathogen control is largely unaltered, suggesting that the role of PTPN22 in the setting of acute LCMV Arm infection is largely dispensable (11).…”

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

“…By contrast, PTPN22 was important for limiting naïve T‐cell responses to weak agonist ova‐peptide variants. Furthermore, several studies have determined that the extent of T‐cell proliferation and activation under lymphopenic conditions in vivo is regulated by PTPN22 . Interestingly, in effector CD8 + cytotoxic T‐cells, the absence of PTPN22 reduced the threshold for activation in response to very low affinity, self‐antigen .…”

Immunopathogenesis of Myasthenia Gravis (Review)

“…В генерации сигналов, передаваемых от полипеп-тидных цепей комплекса TCR-CD3 наиболее важ-но наличие в цитоплазматической части комплекса активационной последовательности ITAM, которая связана с ZAP-70, ключевым фактором в передаче сигнала от TCR при его связывании с лигандом [76,109,111,114]. Кроме CD45, другим ключевым регулятором каскада активации транскрипционных факторов, влияющих на функционирование иммунокомпетентных клеток, является PTPN22 -регулятор иммунного гомеостаза, который ингибирует передачу сигналов Т-клеточного рецептора и селективного промотирования интерфе-ронов типа I, после активации рецепторов влияет на активность ZAP-70 посредством Lck-киназы [29,49]. Следует также отметить, что Т-клеточный рецептор за счет связи с другими молекулами, корецепторами, может передавать как сильные, так и слабые сигна-лы, которые необходимы как для поддержания вы-живания клеток на периферии, так и для создания механизмов аутотолерантности [112].…”