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

Andrew Zloza, Frederick J. Kohlhapp, Gretchen E. Lyons, Jason M. Schenkel, Tamson V. Moore, Andrew T. Lacek, Jeremy A. O'Sullivan, Vineeth Varanasi, Jesse W. Williams, Michael C. Jagoda, Emily C. Bellavance, Amanda L. Marzo, Paul G. Thomas, Biljana Zafirova, Bojan Polić, Lena Al-Harthi, Anne I. Sperling, José A. Guevara-Patiño

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)422-428
Number of pages7
JournalNature Medicine
Issue number3
StatePublished - Mar 2012
Externally publishedYes

Bibliographical note

Funding Information:
US National Cancer Institute Cancer Center Support Grant 5P30CA014599-35) for CD4 depletion antibody production. HMG2D-specific antibody was used with permission from H. Yagita (Juntendo University School of Medicine). This work was supported in part by the American Cancer Society (ACSLIB112496-RSG) to J.A.G.-P.; American Cancer Society-Illinois Division (Young Investigator Award Grant 07-20) to J.A.G.-P.; Croatian Ministry of Science, Education and Sports (062-0621261-1271), as well as the Croatian-Israeli Grant to B.P.; the US National Institutes of Health R21CA127037 and 1P01CA154778-01A1 to J.A.G.-P., PO1AI082971 to L.A.-H., K22AI077714 to P.G.T.; T32 Immunology Training Grant, The University of Chicago, 5T32AI007090 to A.Z., F.J.K. and J.A.O.; and the Cancer Research Foundation (Young Investigator Award) to J.A.G.-P.


Dive into the research topics of 'NKG2D signaling on CD8 + T cells represses T-bet and rescues CD4-unhelped CD8 + T cell memory recall but not effector responses'. Together they form a unique fingerprint.

Cite this