Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic livers.

Human liver CD69⁺CD8⁺ T cells are ∼95% CD103^- and ∼5% CD103⁺. Although CD69⁺CD103⁺CD8⁺ T cells show tissue residency and robustly respond to antigens, CD69⁺CD103^-CD8⁺ T cells are not yet well understood.

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

Human liver CD69⁺CD103^-CD8⁺ T cells exhibited a phenotype of tissue residency and terminal differentiation with HIF-2α upregulation. CD103^- T cells included both hepatotropic and non-hepatotropic viruses-specific cells whereas CD103⁺ T cells did only hepatotropic virus-specific cells. 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 CD69⁺CD8⁺ effector population in the liver, surviving with less cell death. HIF-2α inhibitor suppressed the effector functions and survival of CD69⁺CD103^-CD8⁺ T cells. In addition, HIF-2α expression in liver CD69⁺CD103^-CD8⁺ T cells was significantly increased in patients with AHA or LC.

Liver CD69⁺CD103^-CD8⁺ T cells have the phenotype of tissue residency and terminally differentiation, and their effector functions depends on HIF-2α. Furthermore, activation of liver CD69⁺CD103^-CD8⁺ T cells with HIF-2α upregulation is observed during liver pathology.