{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTHEMIS is a T cell‐specific protein highly expressed during thymocyte development, particularly at the stage between pre–TCR and positive‐selection checkpoints. It plays a critical role in both positive and negative selection, ensuring proper lineage commitment and maturation of T cells. Loss of THEMIS in mice results in impaired thymocyte development, with reductions in transitional CD4⁺CD8^int and single‐positive T cells, underscoring its fundamental role in guiding T cell fate through the integration of subtle TCR signals."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, THEMIS functions as a modulator of early TCR signaling. It is intricately integrated within the LAT signalosome through its constitutive interaction with the adaptor GRB2. This positioning allows THEMIS to recruit tyrosine phosphatases such as SHP1 and SHP2, thereby exerting a negative regulatory influence that dampens TCR-proximal signaling. In some contexts, such as in CAR-T cell synapses, the THEMIS–SHP1 complex attenuates antigen-dependent signaling, highlighting its role in fine-tuning kinase-phosphatase balance and ensuring proper signal strength for T cell survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond thymocyte development, altered THEMIS expression has been implicated in the pathogenesis of immune-mediated diseases. In conditions such as celiac disease, enhanced THEMIS expression in the duodenal mucosa correlates with disease activity, suggesting that proper regulation of THEMIS is essential for maintaining immune homeostasis. Similarly, genetic variants at the THEMIS/PTPRK locus that affect the balance of novel THEMIS isoforms have been linked to multiple sclerosis risk, indicating that dysregulation of THEMIS-dependent signaling may contribute to autoimmunity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Renaud Lesourne, Shoji Uehara, Jan Lee, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Themis controls thymocyte selection through regulation of T cell antigen receptor-mediated signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.1766"}], "href": "https://doi.org/10.1038/ni.1766"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19597499"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19597499"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Claudia Brockmeyer, Wolfgang Paster, David Pepper, et al. "}, {"type": "b", "children": [{"type": "t", "text": "T cell receptor (TCR)-induced tyrosine phosphorylation dynamics identifies THEMIS as a new TCR signalosome component."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.201236"}], "href": "https://doi.org/10.1074/jbc.M110.201236"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21189249"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21189249"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Renaud Lesourne, Ekaterina Zvezdova, Ki-Duk Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interchangeability of Themis1 and Themis2 in thymocyte development reveals two related proteins with conserved molecular function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1200123"}], "href": "https://doi.org/10.4049/jimmunol.1200123"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22732588"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22732588"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Wolfgang Paster, Claudia Brockmeyer, Guo Fu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GRB2-mediated recruitment of THEMIS to LAT is essential for thymocyte development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1203389"}], "href": "https://doi.org/10.4049/jimmunol.1203389"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23460737"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23460737"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Wolfgang Paster, Annika M Bruger, Kristin Katsch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A THEMIS:SHP1 complex promotes T-cell survival."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embj.201387725"}], "href": "https://doi.org/10.15252/embj.201387725"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25535246"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25535246"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Seeyoung Choi, Claude Warzecha, Ekaterina Zvezdova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.3692"}], "href": "https://doi.org/10.1038/ni.3692"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28250424"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28250424"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Chuang Sun, Peishun Shou, Hongwei Du, et al. "}, {"type": "b", "children": [{"type": "t", "text": "THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccell.2019.12.014"}], "href": "https://doi.org/10.1016/j.ccell.2019.12.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32004441"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32004441"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Constanza Bondar, Leticia Plaza-Izurieta, Nora Fernandez-Jimenez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "THEMIS and PTPRK in celiac intestinal mucosa: coexpression in disease and after in vitro gliadin challenge."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2013.136"}], "href": "https://doi.org/10.1038/ejhg.2013.136"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23820479"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23820479"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Jessica L Davies, Sara Thompson, Harpreet Kaur-Sandhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased THEMIS First Exon Usage in CD4+ T-Cells Is Associated with a Genotype that Is Protective against Multiple Sclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0158327"}], "href": "https://doi.org/10.1371/journal.pone.0158327"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27438997"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27438997"}]}]}]}