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

Abstract

ObjectiveTissue-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.DesignWe 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.ResultsHepatic 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.ConclusionsHigh 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.

Hepatic iNKT cells produce type 2 cytokines and restrain antiviral T cells during acute hepacivirus infection

“…As such it would be interesting to also assess a potential role of type 2 iNKT cells or T cell subsets during the chronic stages of NrHV infection. Of note, a recent study identified a subset of IL-4 producing CD4+ T cells in the human liver that correlated with necroinflammatory scores in chronic HBV patients (41).…”

Liver-resident memory T cells: life in lockdown

“…The use of HLA-specific monoclonal antibodies has allowed for the discrimination of liver-resident (donor-derived) and liver infiltrating (recipient-derived) leukocytes in explanted allografts, revealing long-lived Fig. 1 Phenotypic and functional features of human liverresident CD8 + T RM CD4 + and CD8 + T cell progeny maintained within the liver for up to a decade after transplantation into HLAmismatched individuals [47,48]. Intriguingly, such an approach also demonstrated the potential for recipientderived infiltrating T cells to acquire a tissue-residency phenotype once within the liver, thereby contributing to the local pool of resident T cells [47,48].…”

Immunobiology of the biliary tract system

“…44,51 Conventional TCR ab + T cells within the liver are enriched for memory T cells compared with peripheral blood, and the liver CD4/CD8 ratio is skewed towards CD8 T cells. 52,53 Most intrahepatic memory T cells express the tissue-residency marker CD69, while a smaller fraction also coexpress CD103. 52,53 Conventional CD4 and CD8 T cells are present throughout the liver parenchyma but appear enriched in portal areas, although more studies are needed to determine the exact localisation of T cells and their subsets within the liver lobule.…”

“…52,53 Most intrahepatic memory T cells express the tissue-residency marker CD69, while a smaller fraction also coexpress CD103. 52,53 Conventional CD4 and CD8 T cells are present throughout the liver parenchyma but appear enriched in portal areas, although more studies are needed to determine the exact localisation of T cells and their subsets within the liver lobule. 21 Several types of macrophages exist in human and murine livers (Fig.…”