Ptpn22-KO Mouse

PTPN22, protein tyrosine phosphatase non-receptor type 22, is a member of the protein tyrosine phosphatase (PTP) superfamily. It negatively regulates T-cell signaling, playing a key role in immune homeostasis by inhibiting T-cell receptor signalling and selectively promoting type I interferon responses after activation of myeloid-cell pattern-recognition receptors [2,5]. It is also expressed in cells of the innate and adaptive immune systems, and its polymorphisms are associated with multiple autoimmune diseases [3,6].

Using PTPN22-/-mice, studies have shown that PTPN22 deficiency significantly shortens tail-bleeding time and accelerates arterial thrombus formation without affecting venous thrombosis and certain coagulation factors. PTPN22-deficient platelets exhibit enhanced functions such as aggregation, granule secretion, and calcium mobilization. Quantitative phosphoproteomic analysis revealed differences in phosphodiesterase 5A (PDE5A) phosphorylation in these platelets compared to wild-type platelets after stimulation [1]. In T cells, gene editing of the PTPN22 R620W variant showed that loss of PTPN22 function led to enhanced signaling in T cells expressing a lower avidity self-reactive TCR, potentially expanding the self-reactive T cell pool and skewing it toward an inflammatory phenotype [4].

In conclusion, PTPN22 is a crucial regulator in immune-related processes. The use of PTPN22 knockout mouse models has revealed its role in platelet function and arterial thrombosis, as well as in T-cell-related autoimmune disease mechanisms. These findings provide potential targets for preventing thrombotic or cardiovascular diseases and understanding autoimmune diseases [1,4].

References:

1. Wang, Xiamin, Wei, Guangyu, Ding, Yangyang, Xu, Kailin, Qiao, Jianlin. . Protein tyrosine phosphatase PTPN22 negatively modulates platelet function and thrombus formation. In Blood, 140, 1038-1051. doi:10.1182/blood.2022015554. https://pubmed.ncbi.nlm.nih.gov/35767715/

2. Jassim, Brenson A, Lin, Jianping, Zhang, Zhong-Yin. 2022. PTPN22: structure, function, and developments in inhibitor discovery with applications for immunotherapy. In Expert opinion on drug discovery, 17, 825-837. doi:10.1080/17460441.2022.2084607. https://pubmed.ncbi.nlm.nih.gov/35637605/

3. Tizaoui, Kalthoum, Shin, Jae Il, Jeong, Gwang Hun, Koyanagi, Ai, Smith, Lee. 2022. Genetic Polymorphism of PTPN22 in Autoimmune Diseases: A Comprehensive Review. In Medicina (Kaunas, Lithuania), 58, . doi:10.3390/medicina58081034. https://pubmed.ncbi.nlm.nih.gov/36013501/

4. Anderson, Warren, Barahmand-Pour-Whitman, Fariba, Linsley, Peter S, Buckner, Jane H, Rawlings, David J. 2023. PTPN22 R620W gene editing in T cells enhances low-avidity TCR responses. In eLife, 12, . doi:10.7554/eLife.81577. https://pubmed.ncbi.nlm.nih.gov/36961507/

5. Stanford, Stephanie M, Bottini, Nunzio. 2014. PTPN22: the archetypal non-HLA autoimmunity gene. In Nature reviews. Rheumatology, 10, 602-11. doi:10.1038/nrrheum.2014.109. https://pubmed.ncbi.nlm.nih.gov/25003765/

6. Tizaoui, Kalthoum, Terrazzino, Salvatore, Cargnin, Sarah, Shin, Jae Il, Kronbichler, Andreas. 2021. The role of PTPN22 in the pathogenesis of autoimmune diseases: A comprehensive review. In Seminars in arthritis and rheumatism, 51, 513-522. doi:10.1016/j.semarthrit.2021.03.004. https://pubmed.ncbi.nlm.nih.gov/33866147/