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*

*Corresponding author for this work

Research output: Contribution to journalArticle

38 Scopus citations

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-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
Volume18
Issue number3
DOIs
StatePublished - Mar 1 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    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., Polić, B., Al-Harthi, L., Sperling, A. I., & Guevara-Patiño, J. A. (2012). NKG2D signaling on CD8 + T cells represses T-bet and rescues CD4-unhelped CD8 + T cell memory recall but not effector responses. Nature Medicine, 18(3), 422-428. https://doi.org/10.1038/nm.2683