NKG2D signaling on CD8⁺ T cells represses T-bet and rescues CD4-unhelped CD8⁺ T cell memory recall but not effector responses

Nat Med. 2012 Feb 26;18(3):422-8. doi: 10.1038/nm.2683.


CD4-unhelped CD8(+) T cells are functionally defective T cells primed in the absence of CD4(+) T cell help. Given the co-stimulatory role of natural-killer group 2, member D protein (NKG2D) on CD8(+) T cells, we investigated its ability to rescue these immunologically impotent cells. We demonstrate that augmented co-stimulation through NKG2D during priming paradoxically rescues memory, but not effector, CD8(+) T cell responses. NKG2D-mediated rescue is characterized by reversal of elevated transcription factor T-box expressed in T cells (T-bet) expression and recovery of interleukin-2 and interferon-γ production and cytolytic responses. Rescue is abrogated in CD8(+) T cells lacking NKG2D. Augmented co-stimulation through NKG2D confers a high rate of survival to mice lacking CD4(+) T cells in a CD4-dependent influenza model and rescues HIV-specific CD8(+) T cell responses from CD4-deficient HIV-positive donors. These findings demonstrate that augmented co-stimulation through NKG2D is effective in rescuing CD4-unhelped CD8(+) T cells from their pathophysiological fate and may provide therapeutic benefits.

Publication types

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

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cytotoxicity, Immunologic
  • Disease Models, Animal
  • Gene Expression
  • HIV Infections / immunology*
  • HIV-1 / immunology
  • Humans
  • Immunity, Cellular
  • Influenza, Human / genetics
  • Influenza, Human / immunology*
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NK Cell Lectin-Like Receptor Subfamily K / genetics*
  • NK Cell Lectin-Like Receptor Subfamily K / immunology*
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • T-Box Domain Proteins / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology
  • Vaccines, DNA / immunology


  • Interleukin-2
  • Klrk1 protein, mouse
  • NK Cell Lectin-Like Receptor Subfamily K
  • T-Box Domain Proteins
  • Tbx1 protein, mouse
  • Vaccines, DNA
  • Interferon-gamma