Cis-interaction between CD52 and T cell receptor complex interferes with CD4⁺ T cell activation in acute decompensation of cirrhosis

TY - JOUR

T1 - Cis-interaction between CD52 and T cell receptor complex interferes with CD4+ T cell activation in acute decompensation of cirrhosis

AU - Liu, Tong

AU - Wu, Gang

AU - Gudd, Cathrin L.C.

AU - Trovato, Francesca M.

AU - Barbera, Thomas

AU - Liu, Yan

AU - Triantafyllou, Evangelos

AU - McPhail, Mark J.W.

AU - Thursz, Mark R.

AU - Khamri, Wafa

N1 - Publisher Copyright: © 2024 The Authors

PY - 2024/10

Y1 - 2024/10

N2 - 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).

AB - 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).

KW - Acute decompensation

KW - CD4 T cells

KW - CD52

KW - Cirrhosis

KW - Cirrhosis-associated immune dysfunction

KW - T cell receptor

UR - http://www.scopus.com/inward/record.url?scp=85203618906&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2024.105336

DO - 10.1016/j.ebiom.2024.105336

M3 - Article

AN - SCOPUS:85203618906

SN - 2352-3964

VL - 108

JO - EBioMedicine

JF - EBioMedicine

M1 - 105336

ER -