Ptpn2, also called TCPTP (T cell protein tyrosine phosphatase), is a member of the PTP family signaling proteins. Its phosphotyrosine-based signaling is crucial for regulating cell growth, development, differentiation, survival, and migration. Ptpn2 is an essential negative regulator of the JAK/STAT pathways [3,6].

In tumor immunity, in vivo CRISPR screening in mouse transplantable tumours identified Ptpn2 as a cancer immunotherapy target. Deletion of Ptpn2 in tumour cells enhanced interferon-γ-mediated effects on antigen presentation and growth suppression, increasing immunotherapy efficacy [1]. In CD8+ T cells, Ptpn2 deletion increased the generation, proliferative capacity and cytotoxicity of terminally exhausted Tim-3+ cells, enhancing anti-tumor responses and tumor control. Deletion throughout the immune system led to tumor clearance and improved checkpoint blockade responses [4].

In intestinal function, Ptpn2 in macrophages and intestinal epithelial cells (IECs) is required for their interaction to maintain intestinal barrier function. Loss of Ptpn2 from either cell type caused intestinal barrier defects, with a synergistic effect when lost from both [2].

Also, in sepsis, matrine alleviated sepsis symptoms in mice by restraining NLRP3 inflammasome activation through regulating the Ptpn2/JNK/SREBP2 signaling pathway [5].

Moreover, haploinsufficiency in Ptpn2 due to novel monoallelic mutations led to early-onset systemic autoimmunity in patients, with loss of regulatory function and enhanced JAK/STAT signaling [6].

In summary, Ptpn2 plays vital roles in tumor immunity, intestinal barrier function, sepsis response, and autoimmune regulation. Gene knockout (KO) and conditional knockout (CKO) mouse models, along with in vivo studies, have been instrumental in revealing these functions, highlighting Ptpn2 as a potential target for cancer immunotherapy, and providing insights into autoimmune diseases and sepsis treatment [1,2,4,5,6].

References:

1. Manguso, Robert T, Pope, Hans W, Zimmer, Margaret D, Doench, John G, Haining, W Nicholas. 2017. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. In Nature, 547, 413-418. doi:10.1038/nature23270. https://pubmed.ncbi.nlm.nih.gov/28723893/

2. Spalinger, Marianne R, Sayoc-Becerra, Anica, Santos, Alina N, Nair, Meera G, McCole, Declan F. 2020. PTPN2 Regulates Interactions Between Macrophages and Intestinal Epithelial Cells to Promote Intestinal Barrier Function. In Gastroenterology, 159, 1763-1777.e14. doi:10.1053/j.gastro.2020.07.004. https://pubmed.ncbi.nlm.nih.gov/32652144/

3. Song, Jiachun, Lan, Jinxin, Tang, Jiaping, Luo, Na. 2022. PTPN2 in the Immunity and Tumor Immunotherapy: A Concise Review. In International journal of molecular sciences, 23, . doi:10.3390/ijms231710025. https://pubmed.ncbi.nlm.nih.gov/36077422/

4. LaFleur, Martin W, Nguyen, Thao H, Coxe, Matthew A, Haining, W Nicholas, Sharpe, Arlene H. 2019. PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity. In Nature immunology, 20, 1335-1347. doi:10.1038/s41590-019-0480-4. https://pubmed.ncbi.nlm.nih.gov/31527834/

5. Wang, Xu, Wu, Fu-Peng, Huang, Yu-Ran, Sun, Ke-Yu, Shen, Xiao-Yan. 2022. Matrine suppresses NLRP3 inflammasome activation via regulating PTPN2/JNK/SREBP2 pathway in sepsis. In Phytomedicine : international journal of phytotherapy and phytopharmacology, 109, 154574. doi:10.1016/j.phymed.2022.154574. https://pubmed.ncbi.nlm.nih.gov/36610161/

6. Jeanpierre, Marie, Cognard, Jade, Tusseau, Maud, Belot, Alexandre, Mathieu, Anne-Laure. 2024. Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus. In The Journal of experimental medicine, 221, . doi:10.1084/jem.20232337. https://pubmed.ncbi.nlm.nih.gov/39028869/