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Cis-interaction between CD52 and T cell receptor complex interferes with CD4 + T cell activation in acute decompensation of cirrhosis.
- Source :
-
EBioMedicine [EBioMedicine] 2024 Oct; Vol. 108, pp. 105336. Date of Electronic Publication: 2024 Sep 13. - Publication Year :
- 2024
-
Abstract
- 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 <superscript>+</superscript> T cells on the blood of patients with acute decompensation of cirrhosis.<br />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 <superscript>+</superscript> T cells was examined using flow cytometry in CD52 CRISPR-Cas9 knockout primary T cells.<br />Findings: CD52 expression was elevated in CD4 <superscript>+</superscript> 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.<br />Interpretation: Membrane bound CD52 demonstrated cis-interaction with the T cell receptor and served as a dynamic regulator of antigen-specific activation of CD4 <superscript>+</superscript> 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.<br />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).<br />Competing Interests: Declaration of interests Authors disclose no conflicts.<br /> (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Humans
Male
Female
Middle Aged
Aged
Protein Binding
Cytokines metabolism
CD4-Positive T-Lymphocytes immunology
CD4-Positive T-Lymphocytes metabolism
CD52 Antigen metabolism
Lymphocyte Activation immunology
Liver Cirrhosis immunology
Liver Cirrhosis metabolism
Liver Cirrhosis etiology
Receptors, Antigen, T-Cell metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2352-3964
- Volume :
- 108
- Database :
- MEDLINE
- Journal :
- EBioMedicine
- Publication Type :
- Academic Journal
- Accession number :
- 39276679
- Full Text :
- https://doi.org/10.1016/j.ebiom.2024.105336