Upregulation of CD244 promotes CD8+ T cell exhaustion in patients with alveolar echinococcosis and a murine model

In patients with alveolar echinococcosis (AE), CD8.sup.+ T cells undergo functional exhaustion, which accelerates the malignant progression of AE. However, the role of inhibitory receptor CD244 in mediating CD8.sup.+ T cell exhaustion remains elusive. CD244 expression on exhausted CD8.sup.+ T cells in the close liver tissue (CLT) of AE patients was analyzed using single-cell RNA sequencing data. Immunohistochemistry and immunofluorescence were employed to detect CD244 expression. Flow cytometry was used to assess the impact of CD244 on differentiation and effector function of CD8.sup.+ T cells in patients with AE, in vitro and in vivo models. Reactive oxygen species (ROS) and oxygen consumption rate (OCR) were measured to evaluate the influence of CD244 on mitochondrial function of CD8.sup.+ T cells. CD244.sup.+CD8.sup.+ T cells in the CLT of AE patients exhibit a more terminal differentiation phenotype, with reduced secretion of IFN-[gamma] and TNF-[alpha]. In vitro studies revealed that CD8.sup.+ T cells from CD244-deficient mice produced higher levels of IFN-[gamma], TNF-[alpha] and Granzyme B. In vivo studies revealed that CD244 deficiency enhanced the secretion capacity of IFN-[gamma] and TNF-[alpha] by CD8.sup.+ T cells, inhibiting the growth of metacestodes. Moreover, CD244 deficiency leads to a decrease in ROS levels in liver CD8.sup.+ T cells, while significantly increasing their adenosine triphosphate (ATP)-linked oxygen consumption rate. CD244 facilitates AE disease progression by mediating immune exhaustion in CD8.sup.+ T cells.