Themis, a T-lineage-restricted protein, is the founding member of a large metazoan protein family. It plays a critical role in T cell development, especially during thymocyte positive selection, and is involved in signaling downstream of the T cell antigen receptor (TCR) [1,2]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, have been crucial in studying its functions.

In Themis-deficient mice, conventionally positively-selected T-cells are lacking, initially suggesting that Themis positively regulates TCR signaling [2]. However, new data show that Themis deficiency increases TCR signaling, leading to augmented apoptosis [2]. Themis is constitutively bound to the tyrosine phosphatases SHP1 or SHP2, and when recruited onto LAT, it promotes immediate dephosphorylation of TCR-proximal signaling components, setting sharp signaling thresholds [2]. In CD8+ T cells, Themis T-cell conditional knockout mice show that Themis suppresses the effector function of CD8+ T cells in acute viral infection. It mediates PD-1 expression and its signaling in effector CD8+ T cells [3]. Also, in the absence of Themis, the signaling capacity of BTLA is exacerbated, hampering thymocyte positive selection and peripheral CD8+ T cell maintenance [4]. Pharmacologic inhibition of SHP1 or deletion of Ptpn6 (encoding SHP1) ameliorates the positive selection defect in Themis -/- thymocytes, while SHP1 overexpression exacerbates it, supporting the model that Themis enhances the sensitivity of CD4+CD8+ thymocytes to TCR signaling by inhibiting SHP1 activity [5]. Themis is required for IL-2-and IL-15-driven CD8+ T cell proliferation, promoting the activation of Stat and mechanistic target of rapamycin signaling downstream of cytokine receptors [6].

In conclusion, Themis is essential for T cell development and function. KO and CKO mouse models have revealed its role in processes like thymocyte positive selection, CD8+ T cell effector function in viral infection, and cytokine signaling. Understanding Themis provides insights into T cell-related biological processes and potentially, T cell-associated diseases.

References:

1. Choi, Seeyoung, Cornall, Richard, Lesourne, Renaud, Love, Paul E. 2017. THEMIS: Two Models, Different Thresholds. In Trends in immunology, 38, 622-632. doi:10.1016/j.it.2017.06.006. https://pubmed.ncbi.nlm.nih.gov/28697966/

2. Gascoigne, Nicholas R J, Acuto, Oreste. 2015. THEMIS: a critical TCR signal regulator for ligand discrimination. In Current opinion in immunology, 33, 86-92. doi:10.1016/j.coi.2015.01.020. https://pubmed.ncbi.nlm.nih.gov/25700024/

3. Tang, Jian, Jia, Xian, Li, Jian, Gascoigne, Nicholas R J, Fu, Guo. 2023. Themis suppresses the effector function of CD8+ T cells in acute viral infection. In Cellular & molecular immunology, 20, 512-524. doi:10.1038/s41423-023-00997-z. https://pubmed.ncbi.nlm.nih.gov/36977779/

4. Mélique, Suzanne, Vadel, Aurélie, Rouquié, Nelly, Fazilleau, Nicolas, Lesourne, Renaud. 2024. THEMIS promotes T cell development and maintenance by rising the signaling threshold of the inhibitory receptor BTLA. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2318773121. doi:10.1073/pnas.2318773121. https://pubmed.ncbi.nlm.nih.gov/38713628/

5. Choi, Seeyoung, Lee, Jan, Hatzihristidis, Teri, Mikecz, Katalin, Love, Paul E. 2023. THEMIS increases TCR signaling in CD4+CD8+ thymocytes by inhibiting the activity of the tyrosine phosphatase SHP1. In Science signaling, 16, eade1274. doi:10.1126/scisignal.ade1274. https://pubmed.ncbi.nlm.nih.gov/37159521/

6. Liu, Yongchao, Cong, Yu, Niu, Yujia, Lin, Shu-Hai, Fu, Guo. 2022. Themis is indispensable for IL-2 and IL-15 signaling in T cells. In Science signaling, 15, eabi9983. doi:10.1126/scisignal.abi9983. https://pubmed.ncbi.nlm.nih.gov/35167340/