The Capicua/ETS Translocation Variant 5 Axis Regulates Liver-Resident Memory CD8(+) T-Cell Development and the Pathogenesis of Liver Injury

摘要

Liver-resident memory T (liver T-RM) cells exert protective immune responses following liver infection by malaria parasites. However, how these T-RM cells are developed and what the consequence is if they are not properly maintained remain poorly understood. Here, we show that the transcriptional repressor, Capicua (CIC), controls liver CD8(+) T-RM cell development to maintain normal liver function. Cic-deficient mice have a greater number of liver CD8(+) T-RM cells and liver injury phenotypes accompanied by increased levels of proinflammatory cytokine genes in liver tissues. Excessive formation of CD69(+)CD8(+) T-RM-like cells was also observed in mice with acetaminophen-induced liver injury (AILI). Moreover, expansion of liver CD8(+) T-RM cell population and liver injury phenotypes in T-cell-specific Cic null mice were rescued by codeletion of ETS translocation variant [Etv]5 alleles, indicating that Etv5 is a CIC target gene responsible for regulation of CD8(+) T-RM cell development and liver function. We also discovered that ETV5 directly regulates expression of Hobit, a master transcription factor for T-RM cell development, in CD8(+) T cells. Conclusion: Our findings suggest the CIC-ETV5 axis as a key molecular module that controls CD8(+) T-RM cell development, indicating a pathogenic role for CD8(+) T-RM cells in liver injury.