Modulation of CD4+ T cell responses following splenectomy in hepatitis C virus-related liver cirrhosis

N. Hashimoto, S. Shimoda, H. Kawanaka, K. Tsuneyama, H. Uehara, T. Akahoshi, N. Kinjo, A. Taketomi, K. Shirabe, K. Akashi, A. Lleo, A. A. Ansari, M. Eric Gershwin, Y. Maehara

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Dysfunction of T cells is a common feature in chronic persistent viral infections, including hepatitis C virus (HCV), and although hepatic and peripheral T cells have been studied extensively in chronic HCV hepatitis, the role of splenic T cell responses in such patients is poorly defined. This is an important issue, as thrombocytopenia is a complication of HCV-related liver cirrhosis (LC), due to splenic platelet sequestration and bone marrow suppression; splenectomy has been proposed to treat such patients. Herein, we studied peripheral blood mononuclear cells (PBMC) and splenic lymphoid subpopulations from a total of 22 patients, including 15 with HCV-related LC with marked thrombocytopenia treated with splenectomy, and seven controls. CD4+ T cells from peripheral blood and spleen were isolated and phenotype and function evaluated. Splenic CD4+ T cells in patients with LC expressed molecules associated with inhibitory signalling, including increased frequency of negative markers such as cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed death 1 (PD-1) and decreased production of cytokines. Patients with LC manifest higher levels of splenic CD4+ regulatory T cells and PD-L1- and PD-L2-expressing cells than controls. Blocking of PD-1/PD-1 ligand interaction reconstituted proliferative and cytokine responses of splenic mononuclear cells (SMC) from patients with LC. Splenectomy was followed by an increase in the ratio of interferon (IFN)-γ to interleukin (IL)-10 and a reduction of PD-1-expressing CD4+ T cells in peripheral blood. Our data suggest that peripheral tolerance is promoted by the spleen in LC via the up-regulated expression of PD-1 ligands.

Original languageEnglish (US)
Pages (from-to)243-250
Number of pages8
JournalClinical and Experimental Immunology
Volume165
Issue number2
DOIs
StatePublished - Aug 2011

Keywords

  • HCV
  • Liver cirrhosis
  • PD-1
  • PD-1 ligand
  • Splenectomy

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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    Hashimoto, N., Shimoda, S., Kawanaka, H., Tsuneyama, K., Uehara, H., Akahoshi, T., Kinjo, N., Taketomi, A., Shirabe, K., Akashi, K., Lleo, A., Ansari, A. A., Gershwin, M. E., & Maehara, Y. (2011). Modulation of CD4+ T cell responses following splenectomy in hepatitis C virus-related liver cirrhosis. Clinical and Experimental Immunology, 165(2), 243-250. https://doi.org/10.1111/j.1365-2249.2011.04393.x