Cis-interaction between CD52 and T cell receptor complex interferes with CD4+ T cell activation in acute decompensation of cirrhosisResearch in context
Tong Liu,
Gang Wu,
Cathrin L.C. Gudd,
Francesca M. Trovato,
Thomas Barbera,
Yan Liu,
Evangelos Triantafyllou,
Mark J.W. McPhail,
Mark R. Thursz,
Wafa Khamri
Affiliations
Tong Liu
Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom
Gang Wu
Department of Life Sciences, Imperial College London, London, United Kingdom
Cathrin L.C. Gudd
Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom
Francesca M. Trovato
Department of Inflammation Biology, Institute of Liver Studies, King's College London, London, United Kingdom
Thomas Barbera
Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom
Yan Liu
Glycosciences Laboratory, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom
Evangelos Triantafyllou
Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom
Mark J.W. McPhail
Department of Inflammation Biology, Institute of Liver Studies, King's College London, London, United Kingdom
Mark R. Thursz
Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom
Wafa Khamri
Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom; Corresponding author. Imperial College, Liver Immunology Laboratory, Division of Digestive Disease, Department of Metabolism, Digestion & Reproduction, 10th Floor QEQM Wing, St Mary's Campus, South Warf Road, W2 1NY, London, United Kingdom.
Summary: Background: Immune dysfunction contributes to a high rate of infection in patients with acute decompensation of cirrhosis. CD52 is a glycoprotein prominently expressed in lymphocytes. Immune regulation by CD52 may be involved in adaptive immune dysfunction in cirrhosis. This study aimed to investigate the function of CD52 on CD4+ T cells on the blood of patients with acute decompensation of cirrhosis. Methods: The expression of CD52 in the peripheral blood lymphocytes of 49 patients with cirrhosis was investigated using flow cytometry and transcriptomics. Potential cis-membrane ligands of CD52 were discovered via proximity labelling followed by proteomics. The function of CD52 on antigen-specific activation of CD4+ T cells was examined using flow cytometry in CD52 CRISPR-Cas9 knockout primary T cells. Findings: CD52 expression was elevated in CD4+ T cells in acute decompensation of cirrhosis, and this elevation was correlated with increased disease severity and mortality. Components of the T cell receptor complex including TCRβ, CD3γ and CD3ε were identified and validated as cis-membrane ligands of CD52. Knockout of CD52 promoted antigen-specific activation, proliferation, and pro-inflammatory cytokine secretion. Interpretation: Membrane bound CD52 demonstrated cis-interaction with the T cell receptor and served as a dynamic regulator of antigen-specific activation of CD4+ T cells. The upregulation of CD52 in the periphery of acute decompensation of cirrhosis hinders the recognition of the T cell receptor by MHC, contributing to impaired T cell function. The development of an alternative anti-CD52 antibody is required to restore T cell function and prevent infections in cirrhosis. Funding: This study was supported by the NIHR Imperial Biomedical Research Centre, Institute for Translational Medicine and Therapeutics (P74713), Wellcome Trust (218304/Z/19/Z), and Medical Research Council (MR/X009904/1 and MR/R014019/1).
