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Thymocytes from SKG Ptpn22 2/2 show enhanced TCR-induced calcium mobilization compared with SKG mice. (A) Single suspension of BALB/c, SKG, and SKG Ptpn22 2/2 thymocytes was labeled with different concentration of CFSE: 0, 0.012, and 0.002 mM, respectively, mixed in 1:1:1 ratio, and loaded with 2 mM indo-1 dye. Samples were stained with directly conjugated Abs to CD4 (epitope A) and CD8, followed by biotin-conjugated Abs to either TCR-b or CD3 + CD4 (epitope B). Baseline was established for 45 s on gated DP cells, as indicated, and induction of Ca 2+ flux was achieved by addition of cross-linking streptavidin-PE conjugates. Arrows on the histogram indicate the time of addition of streptavidin (45 s) and ionomycin (8 min) as positive control. Data are representative of three independent experiments. (B) Graphs show expression of TCR Vb3, Vb5, Vb11, and Vb8 alleles in gated mature CD4 + CD5 hi thymocytes (left) and peripheral CD4 + T cells (right) for the individual mouse strains, as indicated. The data are representative of three independent experiments and are shown as averages of n = 4 for each strain 6 SD. Statistical significance was calculated by one-way
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The cytoplasmic phosphatase, protein tyrosine phosphatase nonreceptor type 22 (PTPN22), is a negative regulator of T cell signaling. Genome-wide association studies have shown that single-nucleotide polymorphisms in PTPN22 confer an increased risk of developing multiple autoimmune diseases in humans. The precise function of PTPN22 and how the varia...
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... guished by FACS. Cells were stimulated by incubating with bio- tinylated Abs that were cross-linked by addition of streptavidin. Cross-linking CD3 with CD4, but not TCR alone, induced a robust peak of intracellular Ca 2+ flux in WT BALB/c DP thymocytes, whereas Ca 2+ flux in SKG thymocytes was impaired, as has been reported previously (11) (Fig. 2A). The absence of PTPN22 par- tially restored the ability of CD3 plus CD4 cross-linking to induce a Ca 2+ flux in the SKG DP cells, although it remained lower than WT BALB/c control ( Fig. ...
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... robust peak of intracellular Ca 2+ flux in WT BALB/c DP thymocytes, whereas Ca 2+ flux in SKG thymocytes was impaired, as has been reported previously (11) (Fig. 2A). The absence of PTPN22 par- tially restored the ability of CD3 plus CD4 cross-linking to induce a Ca 2+ flux in the SKG DP cells, although it remained lower than WT BALB/c control ( Fig. ...
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... stage (21), we sought to determine whether there was any effect of Ptpn22 deficiency on deletion of these particular TCR Vb families. As described pre- viously (18), the frequency of mature CD4 + single-positive (SP) thymocytes and CD4 + peripheral T cells expressing TCR Vb3, Vb5, or Vb11 chains was increased in SKG as compared with BALB/c mice (Fig. 2B). Additionally, there was a compensatory decrease in the proportion of TCR Vb8.1/8.2 + cells in SKG mice (20). Loss of PTPN22 did not impact on this failure of negative selection on the SKG background, as there was no significant difference in the proportions of these specific TCR Vb-expressing cells in either the thymus or periphery of ...
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... decrease in the proportion of TCR Vb8.1/8.2 + cells in SKG mice (20). Loss of PTPN22 did not impact on this failure of negative selection on the SKG background, as there was no significant difference in the proportions of these specific TCR Vb-expressing cells in either the thymus or periphery of SKG Ptpn22 2/2 com- pared with SKG mice (Fig. 2B). This result agrees with previous studies reporting that PTPN22 has minimal role in negative se- lection (6). Overall, these data indicate that PTPN22 deficiency does not impact substantially on either positive or negative se- lection in the thymus of SKG background mice. We observed a small, but significant increase in ...
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... or efficacy accounted for the reduced arthritis found in the SKG Ptpn22 2/2 mice. TCR signal strength is crucial in development of thymic Tregs (29), and the decrease in TCR signaling capacity in SKG mice results in a decrease in the proportion of thymic Tregs (19). Given that SKG Ptpn22 2/2 mice had slightly improved signaling in DP thymocytes ( Fig. 2A), we asked whether they had any changes in proportions of thymic Tregs. Both the percentages and the abso- lute cell numbers of FoxP3 + cells were similar in the thymuses of SKG Ptpn22 2/2 and SKG mice (Fig. 5A), indicating comparable efficiency of selection of Tregs between these strains. The overall numbers of thymic Tregs in SKG were ...
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... These mice exhibit accumulation of effector memory T cells in aged animals, increased CD4 + T cell help to B cells, expanded follicular helper T cells and germinal centres, and expanded T reg cells with enhanced suppressive and adhesive functions [193][194][195] . PTPN22deficient mice display reduced severity of T H 17-dependent autoimmune arthritis 196 , EAE 194 and anaphylaxis 197 , yet develop more severe DSS-induced colitis [198][199][200] and increased diabetes frequency on the non-obese diabetic background 201 . In lupus models, PTPN22deficient mice display accelerated IFNα-induced lupus-like disease 202 and increased autoantibody production in females in the BXSB model of SLE 203 . ...
Protein phosphatases act as key regulators of multiple important cellular processes and are attractive therapeutic targets for various diseases. Although extensive effort has been dedicated to phosphatase-targeted drug discovery, early expeditions for competitive phosphatase inhibitors were plagued by druggability issues, leading to the stigmatization of phosphatases as difficult targets. Despite challenges, persistent efforts have led to the identification of several drug-like, non-competitive modulators of some of these enzymes — including SH2 domain-containing protein tyrosine phosphatase 2, protein tyrosine phosphatase 1B, vascular endothelial protein tyrosine phosphatase and protein phosphatase 1 — reigniting interest in therapeutic targeting of phosphatases. Here, we discuss recent progress in phosphatase drug discovery, with emphasis on the development of selective modulators that exhibit biological activity. The roles and regulation of protein phosphatases in immune cells and their potential as powerful targets for immuno-oncology and autoimmunity indications are assessed. Dysregulated protein phosphorylation is implicated in numerous human diseases, but targeting protein phosphates has traditionally proved challenging. Here, Stanford and Bottini provide an overview of protein phosphatase families, focusing on their roles in autoimmunity and tumour immunity. Emerging strategies to tackle these targets and agents in development are assessed.
... Serum autoantibodies against citrullinated vimentin, common in RA patients, have been shown to promote osteoclastogenesis and bone resorption [44]. Human cells expressing PTPN22 Trp620 have deficient TLR-induced IFN production, and PTPN22 dysfunction results in lowering thresholds for TCR signaling [46,47]. In a model of IL-1β-dependent synovial inflammation, overexpression of transgenic human PTPN22 Trp620 in mice impaired amelioration of inflammatory arthritis by treatment with an IFN-inducing TLR agonist [47]. ...
... [44] PTPN22 Trp620-expressing human cells have lack of production of TLR-induced IFN production, have lowered threshold for TCR signaling. [46,47] SLE In the C1858T polymorphism of PTPN22, the risk of SLE increased by lowering IFN-gamma rate and higher serum IFN-α activity. [57] The 1858T variant may enhance IFN-α-mediated JAK-STAT signaling, and the increasing number of Pep and IFN-α results in dysfunctional hematopoiesis. ...
It is known that the etiology and clinical outcomes of autoimmune diseases are associated with a combination of genetic and environmental factors. In the case of the genetic factor, the SNPs of the PTPN22 gene have shown strong associations with several diseases. The recent exploding numbers of genetic studies have made it possible to find these associations rapidly, and a variety of autoimmune diseases were found to be associated with PTPN22 polymorphisms. Proteins encoded by PTPN22 play a key role in the adaptative and immune systems by regulating both T and B cells. Gene variants, particularly SNPs, have been shown to significantly disrupt several immune functions. In this review, we summarize the mechanism of how PTPN22 and its genetic variants are involved in the pathophysiology of autoimmune diseases. In addition, we sum up the findings of studies reporting the genetic association of PTPN22 with different types of diseases, including type 1 diabetes mellitus, systemic lupus erythematosus, juvenile idiopathic arthritis, and several other diseases. By understanding these findings comprehensively, we can explain the complex etiology of autoimmunity and help to determine the criteria of disease diagnosis and prognosis, as well as medication developments.
... The most implicated genes conferring risk of RA are (1) the shared epitope (SE), which is encoded by a set of alleles located within the major histocompatibility (MHC) locus, and (2) the PTPN22 polymorphism [3,5], which encodes an abnormal form of lymphoid protein tyrosine phosphatase, an enzyme that inhibits T cell activation [6]. Antigen-presenting cells (APCs) harboring the SE mutant possess enhanced efficiency for presenting citrullinated peptides in their MHC class II molecules [7], whereas T cells harboring the PTPN22 mutant have impaired self-regulation and are prone to remaining in an active state [8]. Additionally, the wild-type form of PTPN22 normally inhibits intracellular citrullination. ...
Rheumatoid arthritis (RA) is an extremely painful autoimmune disease characterized by chronic joint inflammation leading to the erosion of adjacent cartilage and bone. Rheumatoid arthritis pathology is primarily driven by inappropriate infiltration and activation of immune cells within the synovium of the joint. There is no cure for RA. As such, manifestation of symptoms entails lifelong management via various therapies that aim to generally dampen the immune system or impede the function of immune mediators. However, these treatment strategies lead to adverse effects such as toxicity, general immunosuppression, and increased risk of infection. In pursuit of safer and more efficacious therapies, many emerging biomaterial-based strategies are being developed to improve payload delivery, specific targeting, and dose efficacy, and to mitigate adverse reactions and toxicity. In this review, we highlight biomaterial-based approaches that are currently under investigation to circumvent the limitations of conventional RA treatments.Graphical abstract
... In murine models, Ptpn22 deficiency has been associated with increased Treg numbers in both the thymus and the periphery as well as with protection against the induction of experimental autoimmune encephalomyelitis (28,29). Similarly, Ptpn22 deficiency resulted in reduced disease severity and incidence in the SKG mouse *Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL; and † Department of Pediatrics, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL model of rheumatoid arthritis as well as enhanced tolerance of allogeneic islet transplants (30,31). Conversely, although Ptpn22 deficiency does not confer overt autoimmune disease, it has been shown to facilitate autoimmunity when combined with other genetic risk factors, such as hyperactive CD45 E613R mutation, BXSB background, and the KBxN arthritis model (3234). ...
... In all cases, the proliferation of transduced cells was similar to their internal controls (Supplemental Fig. 5B). Similar results were found when CD4 was included in the activation signal to allow for LYP-LCK interactions (Supplemental Fig. 5C, 5D) (30,58). This suggests that optimized signal strength, as well as fluid membrane interface are not sufficient to recapitulate the differential inhibition of proliferation by the two LYP variants, and that other factors supplied by natural APCs (e.g., adhesion molecules, soluble factors, and/or costimulatory and coinhibitory ligand and downstream signaling interactions) may be required (30,58). ...
... Similar results were found when CD4 was included in the activation signal to allow for LYP-LCK interactions (Supplemental Fig. 5C, 5D) (30,58). This suggests that optimized signal strength, as well as fluid membrane interface are not sufficient to recapitulate the differential inhibition of proliferation by the two LYP variants, and that other factors supplied by natural APCs (e.g., adhesion molecules, soluble factors, and/or costimulatory and coinhibitory ligand and downstream signaling interactions) may be required (30,58). ...
A missense mutation (R620W) of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), which encodes lymphoid-tyrosine phosphatase (LYP), confers genetic risk for multiple autoimmune diseases including type 1 diabetes. LYP has been putatively demonstrated to attenuate proximal T and BCR signaling. However, limited data exist regarding PTPN22 expression within primary T cell subsets and the impact of the type 1 diabetes risk variant on human T cell activity. In this study, we demonstrate endogenous PTPN22 is differentially expressed and dynamically controlled following activation. From control subjects homozygous for the nonrisk allele, we observed 2.1- (p < 0.05) and 3.6-fold (p < 0.001) more PTPN22 transcripts in resting CD4+ memory and regulatory T cells (Tregs), respectively, over naive CD4+ T cells, with expression peaking 24 h postactivation. When LYP was overexpressed in conventional CD4+ T cells, TCR signaling and activation were blunted by LYP-620R (p < 0.001) but only modestly affected by the LYP-620W risk variant versus mock-transfected control, with similar results observed in Tregs. LYP overexpression only impacted proliferation following activation by APCs but not anti-CD3- and anti-CD28-coated microbeads, suggesting LYP modulation of pathways other than TCR. Notably, proliferation was significantly lower with LYP-620R than with LYP-620W overexpression in conventional CD4+ T cells but was similar in Treg. These data indicate that the LYP-620W variant is hypomorphic in the context of human CD4+ T cell activation and may have important implications for therapies seeking to restore immunological tolerance in autoimmune disorders.
... In addition to Treg and memory T cells, PTPN22 regulates Th functions. It has been shown that PTPN22 modulates Th17 to Th1/Treg switching [72], though it is dispensable for Th1 generation in vitro in response to CD3 and CD28 stimulation [53]. Individuals homozygous for PTPN22 Trp620 had increased type 1 Th cell-mediated IFN-γ responses and reduced suppression of Th1 cells by Treg cells [57]. ...
... T cell transcriptional suppression by the Treg cell transcription factor, Foxp3 [70] Modulation of T-cell responses via regulation of antigen presenting cell function [59] Negative regulation of the peripheral Treg expansion [53]. Modulation of Th17 to Th1/Treg switching [72] Increased type 1 Th cell-mediated IFN-γ responses and reduced suppression of Th1 cells by Treg cells [57] Reduction of TCR signaling by altering thymic selection, affecting negative selection and development of Foxp3+ T reg cells [50] Alteration of TCR signaling to promote the survival of autoreactive T cells that later participate in self-reactivity [75] ...
The incidence of autoimmune diseases is increasing worldwide, thus stimulating studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors. Genetic association studies have shown the PTPN22 gene as a shared genetic risk factor with implications in multiple autoimmune disorders. By encoding a protein tyrosine phosphatase expressed by the majority of cells belonging to the innate and adaptive immune systems, the PTPN22 gene may have a fundamental role in the development of immune dysfunction. PTPN22 polymorphisms are associated with rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and many other autoimmune conditions. In this review, we discuss the progress in our understanding of how PTPN22 impacts autoimmunity in both humans and animal models. In addition, we highlight the pathogenic significance of the PTPN22 gene, with particular emphasis on its role in T and B cells, and its function in innate immune cells, such as monocytes, dendritic and natural killer cells. We focus particularly on the complexity of PTPN22 interplay with biological processes of the immune system. Findings highlight the importance of studying the function of disease-associated PTPN22 variants in different cell types and open new avenues of investigation with the potential to drive further insights into mechanisms of PTPN22. These new insights will reveal important clues to the molecular mechanisms of prevalent autoimmune diseases and propose new potential therapeutic targets.
... PTPN22 (protein tyrosine phosphatase nonreceptor 22) is a negative regulator of T cell signaling (Sood et al., 2016). In a murine model, PTPN22-/-mice show increased TCR signaling particularly in effector cells (Sood et al., 2016). ...
... PTPN22 (protein tyrosine phosphatase nonreceptor 22) is a negative regulator of T cell signaling (Sood et al., 2016). In a murine model, PTPN22-/-mice show increased TCR signaling particularly in effector cells (Sood et al., 2016). PTPN22 may play a dual role as lack of PTPN22 expression promotes CD8+ T cell activation and cytokine production in a viral murine model but inhibits proliferation ( (Jofra et al., 2016). ...
Mesothelioma is a rare cancer usually affecting the pleura. It is characteristically associated with inhalation of asbestos fibres and accounts for 1% of cancers in the United Kingdom. Median survival remains poor at 4-18 months despite treatment.
Immunotherapy has established itself as an important treatment option in many solid tumours where survival benefit has been shown to be associated with CD8 infiltration. In mesothelioma, there are 3 small studies that suggest that CD8 infiltration may confer survival benefit.
Here, a systematic assessment was undertaken of the prognostic and predictive value of infiltrating adaptive and innate immune cells in a large cohort of patients with advanced mesothelioma. A tissue microarray from 302 samples was constructed. Markers of adaptive immune response CD4+ T helper and CD8+ Cytotoxic T cells, FOXP3+Tregs, CD45RO+Memory T cells and B-cells (CD20+), and innate immune response; macrophages (CD68+), natural killer cells (CD56+) and neutrophils (NP57+) were evaluated.
Surprisingly, CD8+ tumour infiltrating lymphocytes (TILs) did not predict for outcome. On multivariate analysis a high CD4+, high CD20+ and low NP57+ count were linked to better outcome in the epithelioid tumours. A low FOXP3+ predicted for good outcome in both epithelioid and non-epithelioid tumours.
Next, multiplex immunohistochemistry was utilised to further evaluate CD4+ and CD8+ T cell subtypes. This established the presence of MHC class II expression on epithelioid mesothelioma tumour cells and confirmed that some CD4+ T cell subsets (Tissue resident memory cells and T follicular helper cells), were associated with better outcome in epithelioid mesothelioma. The intriguing question of why CD4 + T cells function as the outcome determining immune effectors in mesothelioma, remains to be determined.
Mesothelioma-associated pleural fluid was evaluated to determine its utility as a surrogate for immune events in the solid tumour by transcriptomic analysis. T cells in the pleural fluid exhibited a phenotype characteristic of quiescent/naive cells.
... Both anti-IL-17 and anti-TNFR Abs resulted in reduced arthritis scores compared with the control Ab-treated group in both LACC1 KO and WT mice, indicating that both of these cytokines contribute to arthritis in the MIA model (Fig. 6A), consistent with previous data (16,20). By day 10 after mannan injection, neutralization of IL-17 diminished the differences in arthritis score observed between LACC1 KO and WT mice receiving the control Abs (Fig. 6A, solid lines versus dotted lines, and Fig. 6B). ...
Both common and rare genetic variants of laccase domain-containing 1 (LACC1, previously C13orf31) are associated with inflammatory bowel disease, leprosy, Behcet disease, and systemic juvenile idiopathic arthritis. However, the functional relevance of these variants is unclear. In this study, we use LACC1-deficient mice to gain insight into the role of LACC1 in regulating inflammation. Following oral administration of Citrobacter rodentium, LACC1 knockout (KO) mice had more severe colon lesions compared with wildtype (WT) controls. Immunization with collagen II, a collagen-induced arthritis (CIA) model, resulted in an accelerated onset of arthritis and significantly worse arthritis and inflammation in LACC1 KO mice. Similar results were obtained in a mannan-induced arthritis model. Serum and local TNF in CIA paws and C. rodentium colons were significantly increased in LACC1 KO mice compared with WT controls. The percentage of IL-17A-producing CD4+ T cells was elevated in LACC1 KO mice undergoing CIA as well as aged mice compared with WT controls. Neutralization of IL-17, but not TNF, prevented enhanced mannan-induced arthritis in LACC1 KO mice. These data provide new mechanistic insight into the function of LACC1 in regulating TNF and IL-17 during inflammatory responses. We hypothesize that these effects contribute to immune-driven pathologies observed in individuals carrying LACC1 variants.
... qPCR mix was prepared according to SYBR Green manufacturer protocol (Thermo Fisher). Akt analysis by immunoprecipitation of protein complexes by flow cytometry (IP-FCM) (13), western blotting, and calcium flux protocols have been previously described (14). ...
... Calcium signaling was reported to be enhanced in PTPN22 −/− mouse T cells (10,14,19) and to be diminished in Jurkat cells overexpressing PTPN22 (8). To compare calcium signaling in PTPN22 WT and KO clones, we differentially labeled one clone of each genotype with CFSE, loaded both with Indo-1, and analyzed calcium flux in response to saturating amounts of aqueous anti-CD3 stimulation. ...
... We demonstrate here that the absence of PTPN22 in Jurkat cells leads to enhancement of certain T cell responses. Our findings showed that IL-2 and CD69 upregulation in response to stimulation was significantly enhanced in human T cells lacking PTPN22, which was similarly observed in mouse T cells (4,14,17,20), suggesting that PTPN22 downregulates similar pathways of TCR signaling in human and mouse cells. Our data corroborated those from Perri et al. (21), who reported increased IL-2 expression in human T cells treated with PTPN22-siRNA. ...
A single nucleotide polymorphism, C1858T, in the gene encoding the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) results in one of the strongest genetic traits associated with autoimmune disease outside of the Major Histocompatibility Complex (MHC) genes. However, the consequences of this polymorphism, which introduces an arginine to tryptophan substitution at amino acid 620, for the function of PTPN22 protein is unclear and conflicting results have been obtained in human compared to mouse cells expressing this variant phosphatase. In mouse the variant appears to be a loss-of-function allele resembling a milder form of the null allele, while studies in human cells have reported it to be a gain-of-function mutation. To address whether the phosphatase has distinct functions in mouse vs. human T cells, we used CRISPR gene-editing to generate the first example of human PTPN22-KnockOut (KO) T cells. By comparing isogenic human T cells which express or lack PTPN22, we showed that PTPN22 KO T cells displayed enhanced expression of IL-2 and CD69 upon stimulation with cognate antigen. PTPN22 KO cells also showed increased Erk phosphorylation upon stimulation with weak antigen, but the difference was diminished in response to strong antigen, indicating that PTPN22 plays a more critical role in regulating weak-antigen responses. These data are in keeping with a role for PTPN22 in determining the threshold of stimulation required to activate T cells, a critical function of autoimmune pathogenesis. Our data indicate that PTPN22 has comparable functions in mouse and human T cells, and that the conflicting results in the literature regarding the impact of the point mutation are not due to differences in the activity of PTPN22 itself, but may be related to interactions with other proteins or splice variation.
... In addition to regulating Tcell proliferation, the quality of TCR signalling also determines effector T-cell responses, and perturbations to these pathways are capable of exerting profound effects on the type of immune response initiated [15]. Indeed, multiple studies have observed that, by modulating TCR signalling thresholds, PTPN22 negatively regulates the expansion of peripheral regulatory T-cells [14], and is also capable of modulating Th17 to Th1/Treg switching [16]. Therefore, alterations to PTPN22, as conferred by PTPN22 R620W may impact both the quantity and quality of T-cell immune responses, thereby conferring increased risk of autoimmunity. ...
... For example, overexpression of PTPN22 resulted in attenuated Th1 differentiation at low strength TCR stimulation and protected mice from a model of diabetes [27]. Further studies have demonstrated that PTPN22 is capable of regulating the Th17 bias in mannan immunised SKG mice towards a Th1/Treg phenotype, protecting the mice from arthritis [16]. Although Ptpn22 −/− mice on the C57BL/6 background do not spontaneously develop autoimmunity (due to the enhanced immunosuppressive function of expanded regulatory T cells), our data indicate that over time there is a concomitant expansion in Th1 cells. ...
A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in Ptpn22-/- T-cells and in T-cells from mice expressing Ptpn22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in Ptpn22-/- T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of Ptpn22-/- T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed Ptpn22-/- bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response.
... For example, deleting Src-like adapter protein (SLAP) in SKG mice prevents the development of inflammatory arthritis due to enhanced numbers of Tregs and decreased numbers of Th17 cells (178). Loss of PTPN22 alleviates fungal extract-induced inflammatory arthritis in SKG mice, as PTPN22 deficiency biases T cell differentiation toward Th1 and Treg cells and away from the Th17 lineage (179). ...
T cells possess an array of functional capabilities important for host defense against pathogens and tumors. T cell effector functions require the T cell antigen receptor (TCR). The TCR has no intrinsic enzymatic activity, and thus signal transduction from the receptor relies on additional signaling molecules. One such molecule is the cytoplasmic tyrosine kinase ZAP-70, which associates with the TCR complex and is required for initiating the canonical biochemical signal pathways downstream of the TCR. In this article, we describe recent structure-based insights into the regulation and substrate specificity of ZAP-70, and then we review novel methods for determining the role of ZAP-70 catalytic activity-dependent and -independent signals in developing and mature T cells. Lastly, we discuss the disease states in mouse models and humans, which range from immunodeficiency to autoimmunity, that are caused by mutations in ZAP-70. Expected final online publication date for the Annual Review of Immunology Volume 36 is April 26, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
