Gene Number: 26191

Location: 1p13.2

Key Functions: T-cell receptor signaling regulation, immune tolerance, autoimmunity susceptibility, inflammatory response control

PTPN22 encodes protein tyrosine phosphatase non-receptor type 22 (PTPN22), a cytoplasmic enzyme that serves as a negative regulator of T-cell activation and immune signaling. It plays an essential role in maintaining immune homeostasis by fine-tuning the threshold of T-cell receptor (TCR) activation and ensuring self-tolerance. PTPN22 is predominantly expressed in hematopoietic cells, including T lymphocytes, B cells, and macrophages, where it acts as a key intracellular checkpoint to prevent inappropriate or excessive immune activation.

PTPN22 functions primarily by dephosphorylating key signaling molecules downstream of the TCR, such as Lck, Fyn, and ZAP-70, thereby attenuating T-cell activation once an immune response has been initiated. This action ensures that immune responses are proportionate to pathogenic threats and that self-reactive lymphocytes do not escape immune tolerance mechanisms. Beyond T cells, PTPN22 also modulates B-cell receptor (BCR) and innate immune signaling, contributing to the regulation of cytokine production and antigen presentation.

PTPN22 regulates the immune response through several mechanisms:

1. T-cell activation control:PTPN22 interacts with C-terminal Src kinase (Csk) via its SH3-binding domain, forming the Lyp–Csk inhibitory complex. This complex downregulates early TCR signaling, preventing hyperactivation of T cells and maintaining peripheral tolerance.

   
   

2. B-cell modulation:In B cells, PTPN22 dampens antigen receptor signaling, limiting the survival of autoreactive B cells and preventing the generation of autoantibodies. Dysregulation in this pathway promotes the persistence of B cells that contribute to autoimmune pathogenesis.

   
   

3. Innate immune balance:PTPN22 also influences macrophage and dendritic cell activation by modulating Toll-like receptor (TLR) and NF-κB pathways, ensuring controlled inflammatory cytokine release and balanced immune responses.

   
   

Genetic variation in PTPN22 has profound implications for immune regulation and disease susceptibility. The most studied polymorphism, R620W (rs2476601), results in an arginine-to-tryptophan substitution that disrupts the interaction between PTPN22 and Csk, weakening the inhibitory signaling complex. This leads to enhanced T-cell reactivity, a lower threshold for immune activation, and impaired deletion of autoreactive clones during immune development.

The R620W variant has been robustly associated with increased risk for a wide range of autoimmune diseases, including:

• Type 1 diabetes mellitus (T1D)

• Rheumatoid arthritis (RA)

• Systemic lupus erythematosus (SLE)

• Graves’ disease

• Hashimoto’s thyroiditis

• Vitiligo

• Addison’s disease

  
  

These associations reflect the critical role of PTPN22 in maintaining the balance between immune responsiveness and tolerance. Carriers of the risk allele exhibit heightened autoimmune reactivity due to altered phosphatase regulation, contributing to the breakdown of self-tolerance and chronic inflammation.

PTPN22 thus represents a key immunoregulatory checkpoint, crucial for preventing autoimmunity while allowing effective defense against pathogens. Disruption of its normal function—whether through genetic mutation or post-translational alteration—can shift the immune equilibrium toward pathological activation. Ongoing research aims to develop targeted immunomodulatory therapies that restore proper PTPN22 signaling, offering potential for precision medicine approaches in autoimmune disease management.