Regulation of T Cell Signaling and Immune Responses by PTPN22.

Protein tyrosine phosphatases (PTPs) play central roles in the regulation of cell signaling, organismal development, cellular differentiation and proliferation, and cancer. In the immune system, PTPs regulate the activation, differentiation and effector function of lymphocytes and myeloid cells whilst single-nucleotide polymorphisms (SNPs) in PTP-encoding genes have been identified as risk factors for the development of autoimmunity. In this review we describe the roles for PTP nonreceptor type 22 (PTPN22) in the regulation of T lymphocyte signaling and activation in autoimmunity, infection and cancer.

OT-I TCR Transgenic Mice to Study the Role of PTPN22 in Anti-cancer Immunity.

Phosphotyrosine phosphatase non-receptor type 22 (PTPN22) is a key regulator of immune cell activation and responses. Genetic polymorphisms of PTPN22 have been strongly linked with an increased risk of developing autoimmune diseases, while analysis of PTPN22-deficient mouse strains has determined that PTPN22 serves as a negative regulator of T cell antigen receptor signaling. As well as these key roles in maintaining immune tolerance, PTPN22 acts as an intracellular checkpoint for T cell responses to cancer, suggesting that PTPN22 might be a useful target to improve T cell immunotherapies.

Deletion of the protein tyrosine phosphatase PTPN22 for adoptive T cell therapy facilitates CTL effector function but promotes T cell exhaustion.

Background: Adoptive cell therapy (ACT) is a promising strategy for treating cancer, yet it faces several challenges such as lack of long-term protection due to T cell exhaustion induced by chronic TCR stimulation in the tumor microenvironment. One benefit of ACT, however, is that it allows for cellular manipulations, such as deletion of the phosphotyrosine phosphatase non-receptor type 22 (PTPN22), which improves CD8 T cell antitumor efficacy in ACT. We tested whether cytolytic T cells (CTLs) were also more effective than CTL in controlling tumors in scenarios that favor T cell exhaustion.

Cytokine receptor IL27RA is an NF-κB-responsive gene involved in CD38 upregulation in multiple myeloma.

Multiple myeloma (MM) shows constitutive activation of canonical and noncanonical nuclear factor κB (NF-κB) signaling via genetic mutations or tumor microenvironment (TME) stimulations. A subset of MM cell lines showed dependency for cell growth and survival on the canonical NF-κB transcription factor RELA alone, suggesting a critical role for a RELA-mediated biological program in MM pathogenesis. Here, we determined the RELA-dependent transcriptional program in MM cell lines and found the expression of the cell surface molecules interleukin-27 receptor-α (IL-27Rα) and the adhesion molecule JAM2 to be responsive to RELA at the messenger RNA and protein levels.

Coordination of asparagine uptake and asparagine synthetase expression modulates CD8+ T cell activation.

T cell receptor (TCR) triggering by antigen results in metabolic reprogramming that, in turn, facilitates the exit of T cells from quiescence. The increased nutrient requirements of activated lymphocytes are met, in part, by upregulation of cell surface transporters and enhanced uptake of amino acids, fatty acids, and glucose from the environment. However, the role of intracellular pathways of amino acid biosynthesis in T cell activation is relatively unexplored.

Hematopoietic stem cell gene therapy targeting TGFβ enhances the efficacy of irradiation therapy in a preclinical glioblastoma model.

Patients with glioblastoma (GBM) have a poor prognosis, and inefficient delivery of drugs to tumors represents a major therapeutic hurdle. Hematopoietic stem cell (HSC)-derived myeloid cells efficiently home to GBM and constitute up to 50% of intratumoral cells, making them highly appropriate therapeutic delivery vehicles. Because myeloid cells are ubiquitously present in the body, we recently established a lentiviral vector containing matrix metalloproteinase 14 (MMP14) promoter, which is active specifically in tumor-infiltrating myeloid cells as opposed to myeloid cells in other tissues, and resulted in a specific delivery of transgenes to brain metastases in HSC gene therapy.

Hematopoietic Stem Cell Gene Therapy for Brain Metastases Using Myeloid Cell-Specific Gene Promoters.

Background: Brain metastases (BrM) develop in 20-40% of cancer patients and represent an unmet clinical need. Limited access of drugs into the brain because of the blood-brain barrier is at least partially responsible for therapeutic failure, necessitating improved drug delivery systems.

Methods: Green fluorescent protein (GFP)-transduced murine and nontransduced human hematopoietic stem cells (HSCs) were administered into mice (n = 10 and 3).

Deletion of PTPN22 improves effector and memory CD8+ T cell responses to tumors.

Adoptive T cell therapy (ACT) has been established as an efficacious methodology for the treatment of cancer. Identifying targets to enhance the antigen recognition, functional capacity and longevity of T cells has the potential to broaden the applicability of these approaches in the clinic. We previously reported that targeting expression of phosphotyrosine phosphatase, non-receptor type (PTPN) 22 in effector CD8+ T cells enhances the efficacy of ACT for tumor clearance in mice.

miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity.

The interdependence of selective cues during development of regulatory T cells (Treg cells) in the thymus and their suppressive function remains incompletely understood. Here, we analyzed this interdependence by taking advantage of highly dynamic changes in expression of microRNA 181 family members miR-181a-1 and miR-181b-1 (miR-181a/b-1) during late T-cell development with very high levels of expression during thymocyte selection, followed by massive down-regulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus but simultaneously permitted homeostatic expansion in the periphery in the absence of competition.

Regulation of autoimmune and anti-tumour T-cell responses by PTPN22.

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.

Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8 T cell trafficking.

Inhibition of immune checkpoints programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells results in durable antitumor activity in melanoma patients. Despite high frequency of melanoma brain metastases (BrM) and associated poor prognosis, the activity and mechanisms of immune checkpoint inhibitors (ICI) in metastatic tumors that develop within the "immune specialized" brain microenvironment, remain elusive. We established a melanoma tumor transplantation model with intracranial plus extracranial (subcutaneous) tumor, mimicking the clinically observed coexistence of metastases inside and outside the brain.

Resistance to TGFβ suppression and improved anti-tumor responses in CD8 T cells lacking PTPN22.

Transforming growth factor β (TGFβ) is important in maintaining self-tolerance and inhibits T cell reactivity. We show that CD8 T cells that lack the tyrosine phosphatase Ptpn22, a major predisposing gene for autoimmune disease, are resistant to the suppressive effects of TGFβ. Resistance to TGFβ suppression, while disadvantageous in autoimmunity, helps Ptpn22 T cells to be intrinsically superior at clearing established tumors that secrete TGFβ.

Superresolution imaging of the cytoplasmic phosphatase PTPN22 links integrin-mediated T cell adhesion with autoimmunity.

Integrins are heterodimeric transmembrane proteins that play a fundamental role in the migration of leukocytes to sites of infection or injury. We found that protein tyrosine phosphatase nonreceptor type 22 (PTPN22) inhibits signaling by the integrin lymphocyte function-associated antigen-1 (LFA-1) in effector T cells. PTPN22 colocalized with its substrates at the leading edge of cells migrating on surfaces coated with the LFA-1 ligand intercellular adhesion molecule-1 (ICAM-1).

Loss of the Protein Tyrosine Phosphatase PTPN22 Reduces Mannan-Induced Autoimmune Arthritis in SKG Mice.

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 variant protein contributes to autoimmunity is not well understood.

Mechanistic Target of Rapamycin Complex 1/S6 Kinase 1 Signals Influence T Cell Activation Independently of Ribosomal Protein S6 Phosphorylation.

Ag-dependent activation of naive T cells induces dramatic changes in cellular metabolism that are essential for cell growth, division, and differentiation. In recent years, the serine/threonine kinase mechanistic target of rapamycin (mTOR) has emerged as a key integrator of signaling pathways that regulate these metabolic processes. However, the role of specific downstream effectors of mTOR function in T cells is poorly understood.

Multifunctional roles of the autoimmune disease-associated tyrosine phosphatase PTPN22 in regulating T cell homeostasis.

The non-receptor tyrosine phosphatase PTPN22 has a vital function in inhibiting antigen-receptor signaling in T cells, while polymorphisms in the PTPN22 gene are important risk alleles in human autoimmune diseases. We recently reported that a key physiological function of PTPN22 was to prevent naïve T cell activation and effector cell responses in response to low affinity antigens. PTPN22 also has a more general role in limiting T cell receptor-induced proliferation.

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

T cells must be tolerant of self antigens to avoid autoimmunity but responsive to foreign antigens to provide protection against infection. We found that in both naive T cells and effector T cells, the tyrosine phosphatase PTPN22 limited signaling via the T cell antigen receptor (TCR) by weak agonists and self antigens while not impeding responses to strong agonist antigens. T cells lacking PTPN22 showed enhanced formation of conjugates with antigen-presenting cells pulsed with weak peptides, which led to activation of the T cells and their production of inflammatory cytokines.

T cell receptor signalling networks: branched, diversified and bounded.

Engagement of antigen-specific T cell receptors (TCRs) is a prerequisite for T cell activation. Acquisition of appropriate effector T cell function requires the participation of multiple signals from the T cell microenvironment. Trying to understand how these signals integrate to achieve specific functional outcomes while maintaining tolerance to self is a major challenge in lymphocyte biology.

Lack of the phosphatase PTPN22 increases adhesion of murine regulatory T cells to improve their immunosuppressive function.

The cytoplasmic phosphatase PTPN22 (protein tyrosine phosphatase nonreceptor type 22) plays a key role in regulating lymphocyte homeostasis, which ensures that the total number of lymphocytes in the periphery remains relatively constant. Mutations in PTPN22 confer an increased risk of developing autoimmune diseases; however, the precise function of PTPN22 and how mutations contribute to autoimmunity remain controversial. Loss-of-function mutations in PTPN22 are associated with increased numbers of effector T cells and autoreactive B cells in humans and mice; however, the complete absence of PTPN22 in mice does not result in spontaneous autoimmunity.

Regulation of allograft survival by inhibitory FcγRIIb signaling.

Fcγ receptors (FcγR) provide important immunoregulation. Targeting inhibitory FcγRIIb may therefore prolong allograft survival, but its role in transplantation has not been addressed. FcγRIIb signaling was examined in murine models of acute or chronic cardiac allograft rejection by transplanting recipients that either lacked FcγRIIb expression (FcγRIIb(-/-)) or overexpressed FcγRIIb on B cells (B cell transgenic [BTG]).

LAT polices T cell activation.

Mutations in the adaptor molecule LAT can lead to autoimmunity. In this issue of Immunity, Mingueneau et al. (2009) describe how this may not be a failure of central tolerance.

Distinct cell-specific control of autoimmunity and infection by FcgammaRIIb.

FcgammaRIIb is an inhibitory Fc receptor expressed on B cells and myeloid cells. It is important in controlling responses to infection, and reduced expression or function predisposes to autoimmunity. To determine if increased expression of FcgammaRIIb can modulate these processes, we created transgenic mice overexpressing FcgammaRIIb on B cells or macrophages.

FcgammaRIIb controls bone marrow plasma cell persistence and apoptosis.

The survival of long-lived plasma cells, which produce most serum immunoglobulin, is central to humoral immunity. We found here that the inhibitory Fc receptor FcgammaRIIb was expressed on plasma cells and controlled their persistence in the bone marrow. Crosslinking FcgammaRIIb induced apoptosis of plasma cells, which we propose contributes to the control of their homeostasis and suggests a method for therapeutic deletion.