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

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-? 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. [ABSTRACT FROM AUTHOR]

Copyright of Nature Medicine is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)