Functions of human liver CD69CD103CD8 T cells depend on HIF-2α activity in healthy and pathologic livers.

Background & Aims: Human liver CD69CD8 T cells are ~95% CD103 and ~5% CD103. Although CD69CD103CD8 T cells show tissue residency and robustly respond to antigens, CD69CD103CD8 T cells are not yet well understood.

Methods: Liver perfusate and paired peripheral blood were collected from healthy living donors and recipients with cirrhosis during liver transplantation. Liver tissues were obtained from patients with acute hepatitis A. Phenotypic and functional analyses were performed by flow cytometry. Gene expression profiles were determined by microarray and quantitative reverse transcription PCR. PT-2385 was used to inhibit hypoxia-inducible factor (HIF)-2α.

Results: Human liver CD69CD103CD8 T cells exhibited HIF-2α upregulation with a phenotype of tissue residency and terminal differentiation. CD103 cells comprised non-hepatotropic virus-specific T cells as well as hepatotropic virus-specific T cells, but CD103 cells exhibited only hepatotropic virus specificity. Although CD103 cells were weaker effectors on a per cell basis than CD103 cells, following T cell receptor or interleukin-15 stimulation, they remained the major CD69CD8 effector population in the liver, surviving with less cell death. An HIF-2α inhibitor suppressed the effector functions and survival of CD69CD103CD8 T cells. In addition, HIF-2α expression in liver CD69CD103CD8 T cells was significantly increased in patients with acute hepatitis A or cirrhosis.

Conclusions: Liver CD69CD103CD8 T cells are tissue resident and terminally differentiated, and their effector functions depend on HIF-2α. Furthermore, activation of liver CD69CD103CD8 T cells with HIF-2α upregulation is observed during liver pathology.

Lay Summary: The immunologic characteristics and the role of CD69CD103CD8 T cells, which are a major population of human liver CD8 T cells, remain unknown. Our study shows that these T cells have a terminally differentiated tissue-resident phenotype, and their effector functions depend on a transcription factor, HIF-2α. Furthermore, these T cells were activated and expressed higher levels of HIF-2α in liver pathologies, suggesting that they play an important role in immune responses in liver tissues and the pathogenesis of human liver disease.