Ligand-independent exhaustion of killer immunoglobulin-like receptor-positive CD8+ T cells in human immunodeficiency virus type 1 infection

J Virol. 2008 Oct;82(19):9668-77. doi: 10.1128/JVI.00341-08. Epub 2008 Jun 25.

Abstract

Virus-specific CD8(+) T cells play a central role in the control of viral infections, including human immunodeficiency virus type 1 (HIV-1) infection. However, despite the presence of strong and broad HIV-specific CD8(+) T-cell responses in chronic HIV-1 infection, these cells progressively lose critical effector functions and fail to clear the infection. Mounting evidence suggests that the upregulation of several inhibitory regulatory receptors on the surface of CD8(+) T cells during HIV-1 infection may contribute directly to the impairment of T-cell function. Here, we investigated the role of killer immunoglobulin receptors (KIR), which are expressed on NK cells and on CD8(+) T cells, in regulating CD8(+) T-cell function in HIV-1 infection. KIR expression was progressively upregulated on CD8(+) T cells during HIV-1 infection and correlated with the level of viral replication. Expression of KIR was associated with a profound inhibition of cytokine secretion, degranulation, proliferation, and activation by CD8(+) T cells following stimulation with T-cell receptor (TCR)-dependent stimuli. In contrast, KIR(+) CD8(+) T cells responded potently to TCR-independent stimulation, demonstrating that these cells are functionally competent. KIR-associated suppression of CD8(+) T-cell function was independent of ligand engagement, suggesting that these regulatory receptors may constitutively repress TCR activation. This ligand-independent repression of TCR activation of KIR(+) CD8(+) T cells may represent a significant barrier to therapeutic interventions aimed at improving the quality of the HIV-specific CD8(+) T-cell response in infected individuals.

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*
  • Case-Control Studies
  • Cell Membrane / metabolism
  • Cell Membrane / virology*
  • Cell Proliferation
  • Cytokines / metabolism
  • HIV Infections / metabolism*
  • HIV-1 / metabolism*
  • Humans
  • Leukocytes, Mononuclear / cytology
  • Ligands*
  • Lymphocyte Activation
  • Receptors, KIR / metabolism*
  • T-Lymphocytes / metabolism
  • Virus Diseases / immunology
  • Virus Replication

Substances

  • Cytokines
  • Ligands
  • Receptors, KIR