The human liver microenvironment shapes the homing and function of CD4 ⁺ T-cell populations

ABSTRACT Background & Aims Tissue-resident memory T cells (T RM ) are important immune sentinels that provide efficient in situ immunity. Liver-resident CD8 + T RM have been previously described, and contribute to viral control in persistent hepatotropic infections. However, little is known regarding liver CD4 + T RM cells. Here we profiled resident and non-resident intrahepatic CD4 + T cell subsets, assessing their phenotype, function, differential generation requirements and roles in hepatotropic infection. Methods Liver tissue was obtained from 173 subjects with (n=109) or without (n=64) hepatic pathology. Multiparametric flow cytometry and immunofluorescence imaging examined T cell phenotype, functionality and location. Liver T cell function was determined after stimulation with anti-CD3/CD28 and PMA/Ionomycin. Co-cultures of blood-derived lymphocytes with hepatocyte cell lines, primary biliary epithelial cells, and precision-cut autologous liver slices were used to investigate the acquisition of liver-resident phenotypes. Results CD69 expression delineated two distinct subsets in the human liver. CD69 HI cells were identified as CD4 + T RM due to exclusion from the circulation, a residency-associated phenotype (CXCR6 + CD49a + S1PR1 - PD-1 + ), restriction to specific liver niches, and ability to produce robust type-1 multifunctional cytokine responses. Conversely, CD69 INT were an activated T cell population also found in the peripheral circulation, with a distinct homing profile (CX 3 CR1 + CXCR3 + CXCR1 + ), and a bias towards IL-4 production. Frequencies of CD69 INT cells correlated with the degree of fibrosis in chronic hepatitis B virus infection. Interaction with hepatic epithelia was sufficient to generate CD69 INT cells, while additional signals from the liver microenvironment were required to generate liver-resident CD69 HI cells. Conclusions Intermediate and high CD69 expression demarcates two discrete intrahepatic CD4 + T cell subsets with distinct developmental and functional profiles. Graphical Abstract Highlights CD69 HI (CXCR6 + CD49a + S1PR1 - PD-1 + ) are the CD4 + T RM of the human liver Hepatic CD69 INT CD4 + T-cells are distinct, activated, and recirculation-competent Stimulation evokes respective IFN-γ and IL-4 responses in CD69 HI and CD69 INT cells CD69 INT cell frequencies correlate with worsening fibrosis in chronic HBV patients Liver slice cultures allow differentiation of CD69 INT and CD69 HI cells from blood Lay summary Tissue-resident memory T cells (T RM ) orchestrate regional immune responses, but much of the biology of liver-resident CD4 + T RM remains unknown. We found high expression of cell-surface protein CD69 defined hepatic CD4 + T RM , while simultaneously uncovering a distinct novel recirculatory CD69 INT CD4 + T cell subset. Both subsets displayed unique immune receptor profiles, were functionally skewed towards type-1 and type-2 responses respectively, and had distinct generation requirements, highlighting the potential for differential roles in the immunopathology of chronic liver diseases.

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