Themis, a T-lineage-restricted protein, is the founding member of a large metazoan protein family. It is crucial for thymocyte positive selection and is involved in signaling downstream of the T cell antigen receptor (TCR), playing a significant role in T cell development [1,2].

Genetic approaches, especially using gene knockout (KO) mouse models, have revealed multiple functions of Themis. In Themis-deficient mice, the absence of conventionally positively-selected T-cells led to initial hypotheses about its role in positively regulating TCR signaling [2]. Further studies showed that Themis deficiency increased TCR signaling, resulting in augmented apoptosis [2]. Themis -/- thymocytes' positive selection defect was ameliorated by SHP1 inhibition or Ptpn6 deletion, indicating that Themis may enhance CD4+CD8+ thymocytes' sensitivity to TCR signaling by inhibiting SHP1 [4]. In CD8+ T cells, Themis-T-cell conditional knockout mice demonstrated that Themis suppresses effector function during acute viral infection, promoting memory precursor cell differentiation and regulating cytokine production [3]. Also, Themis is indispensable for IL-2 and IL-15 signaling in T cells, as Themis deficiency reduced T cell proliferation, glycolysis, and biosynthesis [5].

In conclusion, Themis plays essential roles in T cell development and function. Themis KO and conditional knockout (CKO) mouse models have been instrumental in revealing its functions in thymocyte positive selection, CD8+ T cell effector function during viral infection, and cytokine signaling in T cells. These findings contribute to understanding T cell-related biological processes and potentially relevant disease mechanisms.