Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS

Nature. 2023 Feb;614(7947):334-342. doi: 10.1038/s41586-022-05645-6. Epub 2023 Jan 25.

Abstract

The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours1-4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+ T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14high myeloid cells in hepatic zone 2. CD14+CD8+ T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+ T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14+CD8+ T cell profile can be recapitulated by the acquisition of membrane proteins-including the lipopolysaccharide receptor complex-from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14+CD8+ T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14+CD8+ T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut-liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+ T cells with immunomodulatory ability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacteria / immunology
  • CD8-Positive T-Lymphocytes* / cytology
  • CD8-Positive T-Lymphocytes* / drug effects
  • CD8-Positive T-Lymphocytes* / immunology
  • CD8-Positive T-Lymphocytes* / metabolism
  • Chemotaxis, Leukocyte
  • Humans
  • Immune Tolerance* / drug effects
  • Immune Tolerance* / immunology
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / immunology
  • Intestines / immunology
  • Intestines / microbiology
  • Lipopolysaccharide Receptors* / metabolism
  • Lipopolysaccharides* / immunology
  • Lipopolysaccharides* / pharmacology
  • Liver* / drug effects
  • Liver* / immunology
  • Liver* / pathology
  • Liver* / virology
  • Myeloid Cells* / immunology
  • Myeloid Cells* / metabolism
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism

Substances

  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Receptors, Antigen, T-Cell
  • CD14 protein, human
  • IL10 protein, human
  • Interleukin-2
  • CXCL12 protein, human