Epithelial adhesion molecules can inhibit HIV-1-specific CD8⁺ T-cell functions

Blood. 2011 May 12;117(19):5112-22. doi: 10.1182/blood-2010-12-321588. Epub 2011 Mar 14.

Abstract

Under persistent antigenic stimulation, virus-specific CD8⁺ T cells become increasingly dysfunctional and up-regulate several inhibitory molecules such as killer lectin-like receptor G1 (KLRG1). Here, we demonstrate that HIV-1 antigen-specific T cells from subjects with chronic-progressive HIV-1 infection have significantly elevated KLRG1 expression (P < .001); show abnormal distribution of E-cadherin, the natural ligand of KLRG1, in the intestinal mucosa; and have elevated levels of systemic soluble E-cadherin (sE-cadherin) that significantly correlate with HIV-1 viral load (R = 0.7, P = .004). We furthermore demonstrate that in the presence of sE-cadherin, KLRG1(hi) HIV-1-specific CD8⁺ T cells are impaired in their ability to respond by cytokine secretion on antigenic stimulation (P = .002) and to inhibit viral replication (P = .03) in vitro. Thus, these data suggest a critical mechanism by which the disruption of the intestinal epithelium associated with HIV-1 leads to increased systemic levels of sE-cadherin, which inhibits the effector functions of KLRG1(hi)-expressing HIV-1-specific CD8⁺ T cells systemically.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cadherins / immunology
  • Cadherins / metabolism*
  • Cell Adhesion Molecules / immunology
  • Cell Adhesion Molecules / metabolism
  • Cell Separation
  • Colon / immunology
  • Colon / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • HIV Infections / immunology*
  • HIV Infections / metabolism
  • HIV-1 / immunology
  • Humans
  • Immunohistochemistry
  • Lectins, C-Type / biosynthesis*
  • Lectins, C-Type / immunology
  • Lymphocyte Activation / immunology
  • Male
  • Receptors, Immunologic
  • Trans-Activators / biosynthesis*
  • Trans-Activators / immunology
  • Virus Replication / immunology

Substances

  • Cadherins
  • Cell Adhesion Molecules
  • KLRG1 protein, human
  • Lectins, C-Type
  • Receptors, Immunologic
  • Trans-Activators