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CD4+ T cells license Kupffer cells to reverse the CD8+ T cell dysfunction induced by hepatocellular priming

ABSTRACT: CD4⁺ T cells are believed to be essential for effective CD8⁺ T cell responses against hepatotropic viruses like hepatitis B virus (HBV). However, the specific locations and the cellular and molecular mechanisms through which CD4⁺ T cells help CD8⁺ T cells remain unclear. In this study, we generated HBV-specific CD4⁺ TCR transgenic mice to demonstrate that effector CD4⁺ T cells can prevent or reverse the dysfunction of CD8⁺ T cells caused by hepatocellular priming. This, in turn, enhances CD8⁺ T cell effector function and suppresses viral replication. Notably, CD4⁺ T cell help to CD8+ T cells occurs directly in the liver, independent of secondary lymphoid organs, and requires local antigen recognition but not epitope linkage. While dendritic cells were found to be dispensable, Kupffer cells (KCs) emerged as the critical cellular platform for this effect. Mechanistically, CD4⁺ T cells engage KCs via CD40-CD40L interactions, leading to the production of IL-12 and IL-27. IL-12 promotes further CD4⁺ T cell expansion, whereas IL-27 serves as the key cytokine that restores CD8⁺ T cell functionality. Furthermore, we show that exogenous IL-27 administration can reverse HBV-specific CD8⁺ T cell dysfunction in mice and in chronically infected patients. These findings reveal a novel mechanism of CD4⁺ T cell help to CD8⁺ T cells that occurs outside secondary lymphoid organs, specifically in the liver, and involves antigen-presenting cells other than conventional dendritic cells, offering new insights for immunotherapeutic strategies against chronic HBV infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE283038 | GEO | 2025/05/03

REPOSITORIES: GEO

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Project description:Innate immune responses are important in combating various microbes during the early phases of infection. Natural killer (NK) cells are innate lymphocytes that, unlike T and B lymphocytes, do not express antigen receptors but rapidly exhibit cytotoxic activities against virus infected cells and produce various cytokines1,2. We report here a new type of innate lymphocyte present in a novel lymphoid structure associated with adipose tissues in the peritoneal cavity. These cells do not express lineage (Lin) markers but express c-Kit, Sca-1, IL-7R and IL-33R. Similar lymphoid clusters were found in both human and mouse mesentery and we term this tissue â??FALCâ?? for fat-associated lymphoid cluster. FALC Lin-c-Kit+Sca-1+ cells are distinct from lymphoid progenitors3 and lymphoid tissue inducer (LTi) cells4. These cells proliferate in response to IL-2 and produce large amounts of Th2 cytokines such as IL-5, IL-6 and IL-13. IL-5 and IL-6 regulate B cell antibody production and self-renewal of B1 cells5-7. Indeed, FALC Lin-c-Kit+Sca-1+ cells support the self-renewal of B1 cells and enhance IgA production. IL-5 and IL-13 mediate allergic inflammation and protection against helminth infection8,9. Upon helminth infection and in response to IL-33, FALC Lin-c-Kit+Sca-1+ cells produce large amounts of IL-13, which leads to goblet cell hyperplasia, a critical step for helminth expulsion. In mice devoid of FALC Lin-c-Kit+Sca-1+ cells such goblet cell hyperplasia was not induced. Thus, FALC Lin-c-Kit+Sca-1+ cells are Th2-type innate lymphocytes and we propose that these cells be called â??natural helper cellsâ??. Experiment Overall Design: Natural helper cells (Lin- c-kit+ Sca-1+) were isolated from mesentery of C57BL/6 for RNA extraction and hybridization on Affymetrix microarrays. For the control of this experiment, we use double negative cells (DN2) from thymus of C57BL/6 or lymphoid tissue inducer cells (LTi). Thymic DN2 cells were prepared from adult thymocytes. Thymocytes were stained with magnetic beads conjugated with anti-CD4 and anti-CD8Î± mAbs and CD4-CD8- double negative (DN) cells were negatively sorted by AutoMACS. DN cells were further stained with anti-CD25 and anti-CD44 mAbs and CD25+CD44+ cells were sorted as DN2 cells on a FACSAria.Thy-1+CD4- LTi cells were prepared from fetal liver cells as described previously. c-Kit+Î±4Î²7+IL-7RÎ±+ fetal liver cells from day 13 embryos were cultured on TSt4 cells for 17 days.

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CD4+ T cells license Kupffer cells to reverse the CD8+ T cell dysfunction induced by hepatocellular priming

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