The liver is highly exposed to bacteria and bacterial products such as lipopolysaccharide (LPS) from the intestine, directed via the portal vein. To prevent an uncontrolled immune response, the liver maintains a certain state of tolerance. However, despite this phenomenon, known as “liver tolerance”, the composition of the intestinal microbiome or LPS content, may contribute to the development and progression of liver diseases, including hepatocellular carcinoma.
“There is a delicate balance between the functions of tolerance and immune surveillance, which prevents the spread of pathogens. Identifying and understanding the cellular mechanisms that modulate both these processes is key to developing immunotherapies to treat liver diseases”, says Sofía Pérez del Pulgar and Sabela Lens, researchers in the IDIBAPS research group on Viral, genetic and immune-mediated liver diseases, whose leader is Xavier Forns. Pérez del Pulgar and Lens are participants in a study, published in the journal Nature, which analyses the unique characteristics of CD14+CD8+T cells in the human liver. “The research aims to determine which local mechanisms and components induce the reprogramming of these immune system cells after acquiring organ residency, that is to say, once the cells have adapted to the liver to perform immunoregulatory functions”.
Using imaging mass cytometry on human liver samples, the researchers observed that CD14+CD8+ T cells are in close contact with myeloid cells, monocytes and macrophages, in the liver. “Via this interaction, monocytes and macrophages transfer the CD14 molecule, a component of the receptor that recognises LPS, and other prototypical myeloid markers from their membrane to the membrane of CD8+ T lymphocytes”, explains Pérez del Pulgar. Confirmation that the subpopulation of memory CD8+ T cells resident in the liver is long-lived but can be supplemented by circulating cells was described in 2020 in a study in which Clínic Barcelona-IDIBAPS also took part. The study was led by Mala Maini of University College London, who also leads the present study. In it, say the researchers,“our laboratory has contributed to the observation that bacterial LPS modulates the formation of CD14+CD8+ T cells through a model of cirrhosis with ascites and spontaneous bacterial peritonitis".
Due to this reprogramming, the CD14+CD8+ T cells present a highly activated phenotype. “The antiviral and antitumour activity of the cells is significantly enhanced. The cells also constantly secrete cytokines, such as IL-10 and IL-2, which modulate the immune system, and acquire the ability to respond directly to the presence of LPS”, say the researchers.
Similarly, in transplant recipients, most of the CD8+ T cells from the donor are eliminated, but the CD14+CD8+ T cells persist and are still detectable 11 years after transplantation. “What is interesting is that the recipient’s CD8+T cells which infiltrate the transplanted liver do not acquire CD14 expression, despite being in contact with the donor cells for years. This seems to confirm the role of myeloid cells in reprogramming T lymphocytes. In terms of clinical practice, this finding has important implications for immunotherapy, as myeloid reprogramming could be applied in the optimisation of T-cell therapies”, concludes Pérez del Pulgar.
Reference article
Pallett LJ, Swadling L, Diniz M, Maini AA, Schwabenland M, Gasull AD, Davies J, Kucykowicz S, Skelton JK, Thomas N, Schmidt NM, Amin OE, Gill US, Stegmann KA, Burton AR, Stephenson E, Reynolds G, Whelan M, Sanchez J, de Maeyer R, Thakker C, Suveizdyte K, Uddin I, Ortega-Prieto AM, Grant C, Froghi F, Fusai G, Lens S, Pérez-Del-Pulgar S, Al-Akkad W, Mazza G, Noursadeghi M, Akbar A, Kennedy PTF, Davidson BR, Prinz M, Chain BM, Haniffa M, Gilroy DW, Dorner M, Bengsch B, Schurich A, Maini MK. 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.