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

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Authors: Zloza, A.; Kohlhapp, F. J.; Lyons, G. E.; Schenkel, J. M.; Moore, T. V.; Lacek, A. T.; O'Sullivan, J. A.; Varanasi, V.; Williams, J. W.; Jagoda, M. C.; Bellavance, E. C.; Marzo, A. L.; Thomas, P. G.; Zafirova, B.; Polic, B.; Al-Harthi, L.; Sperling, A. I.; Guevara-Patino, J. A.
Article Title: NKG2D signaling on CD8(+) T cells represses T-bet and rescues CD4-unhelped CD8(+) T cell memory recall but not effector responses
Abstract: 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-gamma 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.
Journal Title: Nature medicine
Volume: 18
Issue: 3
ISSN: 1546-170X; 1078-8956
Publisher: Unknown  
Journal Place: United States
Date Published: 2012
Start Page: 422
End Page: 428
Language: eng
DOI/URL:

10.1038/nm.2683

10.1038/nm.2683
Notes: LR: 20130626; GR: 5P30CA014599-35/CA/NCI NIH HHS/United States; GR: 5T32AI007090/AI/NIAID NIH HHS/United States; GR: K22AI077714/AI/NIAID NIH HHS/United States; GR: P01AI082971/AI/NIAID NIH HHS/United States; GR: R21 CA127037/CA/NCI NIH HHS/United States; GR: R21CA127037/CA/NCI NIH HHS/United States; JID: 9502015; 0 (Interleukin-2); 0 (Klrk1 protein, mouse); 0 (NK Cell Lectin-Like Receptor Subfamily K); 0 (T-Box Domain Proteins); 0 (Tbx1 protein, mouse); 0 (Vaccines, DNA); 82115-62-6 (Interferon-gamma); NIHMS399158; OID: NLM: NIHMS399158; OID: NLM: PMC3436127; 2011/11/10 [received]; 2012/01/20 [accepted]; 2012/02/26 [aheadofprint]; epublish