The Capicua‐ETV5 axis regulates liver‐resident memory CD8+ T cell development and the pathogenesis of liver injury

Abstract

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 is the consequence 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 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, the expansion of liver CD8⁺ T_RM cell population and the liver injury phenotypes in T cell‐specific Cic null mice were rescued by co‐deletion of Etv5 alleles, indicating that Etv5 is a CIC target gene responsible for the regulation of CD8⁺ T_RM cell development and liver function. We also discovered that ETV5 directly regulates the expression of Hobit, a master transcription factor for T_RM cell development, in CD8⁺ T cells.

Conclusion

Our findings not only suggest that the CIC‐ETV5 axis is a key molecular module that controls CD8⁺ T_RM cell development, but also uncover a previously‐unrecognized pathogenic role for CD8⁺ T_RM cells in liver injury.

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