PT - JOURNAL ARTICLE AU - Benjamin G Wiggins AU - Laura J Pallett AU - Xiaoyan Li AU - Scott P Davies AU - Oliver E Amin AU - Upkar S Gill AU - Stephanie Kucykowicz AU - Arzoo M Patel AU - Konstantinos Aliazis AU - Yuxin S Liu AU - Gary M Reynolds AU - Brian R Davidson AU - Amir Gander AU - Tu Vinh Luong AU - Gideon M Hirschfield AU - Patrick T F Kennedy AU - Yuehua Huang AU - Mala K Maini AU - Zania Stamataki TI - The human liver microenvironment shapes the homing and function of CD4<sup>+</sup> T-cell populations AID - 10.1136/gutjnl-2020-323771 DP - 2022 Jul 01 TA - Gut PG - 1399--1411 VI - 71 IP - 7 4099 - http://gut.bmj.com/content/71/7/1399.short 4100 - http://gut.bmj.com/content/71/7/1399.full SO - Gut2022 Jul 01; 71 AB - Objective Tissue-resident memory T cells (TRM) are vital immune sentinels that provide protective immunity. While hepatic CD8+ TRM have been well described, little is known about the location, phenotype and function of CD4+ TRM.Design We used multiparametric flow cytometry, histological assessment and novel human tissue coculture systems to interrogate the ex vivo phenotype, function and generation of the intrahepatic CD4+ T-cell compartment. We also used leukocytes isolated from human leukocyte antigen (HLA)-disparate liver allografts to assess long-term retention.Results Hepatic CD4+ T cells were delineated into three distinct populations based on CD69 expression: CD69−, CD69INT and CD69HI. CD69HICD4+ cells were identified as tissue-resident CD4+ T cells on the basis of their exclusion from the circulation, phenotypical profile (CXCR6+CD49a+S1PR1−PD-1+) and long-term persistence within the pool of donor-derived leukcoocytes in HLA-disparate liver allografts. CD69HICD4+ T cells produced robust type 1 polyfunctional cytokine responses on stimulation. Conversely, CD69INTCD4+ T cells represented a more heterogenous population containing cells with a more activated phenotype, a distinct chemokine receptor profile (CX3CR1+CXCR3+CXCR1+) and a bias towards interleukin-4 production. While CD69INTCD4+ T cells could be found in the circulation and lymph nodes, these cells also formed part of the long-term resident pool, persisting in HLA-mismatched allografts. Notably, frequencies of CD69INTCD4+ T cells correlated with necroinflammatory scores in chronic hepatitis B infection. Finally, we demonstrated that interaction with hepatic epithelia was sufficient to generate CD69INTCD4+ T cells, while additional signals from the liver microenvironment were required to generate liver-resident CD69HICD4+ T cells.Conclusions High and intermediate CD69 expressions mark human hepatic CD4+ TRM and a novel functionally distinct recirculating population, respectively, both shaped by the liver microenvironment to achieve diverse immunosurveillance.Data are available upon reasonable request.