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

Nature Medicine volume 18, pages 422–428 (2012)Cite this article

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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.

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Figure 1: NKG2D engagement by Rae-1ɛ rescues CD4-unhelped CD8+ T cell memory-recall expansion.
Figure 2: NKG2D-mediated rescue of CD4-unhelped CD8+ T cell memory-recall responses involves cytokine and lytic molecule production and lytic activity.
Figure 3: Rescue of CD4-unhelped CD8+ T cell memory-recall responses is dependent on NKG2D expression on CD8+ T cells.
Figure 4: NKG2D engagement reverses the elevated T-bet expression associated with CD4-unhelped CD8+ T cells.
Figure 5: Suppression of T-bet by NKG2D–Rae-1ɛ engagement is mediated through JNK2.
Figure 6: NKG2D co-stimulation confers protection in CD4-dependent infectious disease models.

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  • 07 October 2013

     In the version of this article initially published, a funding source, P01CA154778-01A1 to J.A.G.-P., was omitted from the Acknowledgments. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

For their kind gifts, we thank: A. Houghton (pCRAN vector and OVA DNA; Memorial Sloan-Kettering Cancer Center); V. Kumar and L. Chlewicki (non–Rae-1ɛ–expressing EL-4 cells; The University of Chicago); L. Lanier (genes encoding Rae-1ɛ, Rae-1ɛ–GFP, and H60; University of California, San Francisco); A. Tenorio (HIV-positive donor identification; Rush University Medical Center); W. Yokoyama (NKG2D-deficient mouse spleens; Washington University School of Medicine in St. Louis), and D. Raulet (NKG2D-decifient mice, University of California, Berkeley). We thank B. Jabri, A. Bendelac, M.I. Nishimura and M.J. Turk for constructive discussions and manuscript edits. We are grateful to the flow cytometry facilities at The University of Chicago and at Loyola University Chicago for their invaluable support and to the Frank W. Fitch Monoclonal Antibody Facility of The University of Chicago Cancer Center (funded by 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 P01CA154778-01A1 to J.A.G.-P., 1PO1AI082971 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.

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Author notes

  1. Andrew Zloza, Frederick J Kohlhapp and Gretchen E Lyons: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Committee on Immunology, The University of Chicago, Chicago, Illinois, USA

    Andrew Zloza, Frederick J Kohlhapp, Gretchen E Lyons, Tamson V Moore, Andrew T Lacek, Jeremy A O'Sullivan, Michael C Jagoda, Emily C Bellavance & José A Guevara-Patiño

  2. Department of Surgery, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois, USA

    Andrew Zloza, Tamson V Moore, Jeremy A O'Sullivan & José A Guevara-Patiño

  3. Department of Microbiology, Center for Immunology, University of Minnesota, Minneapolis, Minnesota, USA

    Jason M Schenkel

  4. Department of Pathology, Committee on Immunology, The University of Chicago, Chicago, Illinois, USA

    Vineeth Varanasi

  5. Department of Medicine, Section of Pulmonary and Critical Care Medicine, Committee on Immunology, The University of Chicago, Chicago, Illinois, USA

    Jesse W Williams & Anne I Sperling

  6. Department of Immunology/Microbiology and Developmental Center for AIDS Research, Rush University Medical Center, Chicago, Illinois, USA

    Amanda L Marzo & Lena Al-Harthi

  7. Rush University Cancer Center, Rush University Medical Center, Chicago, Illinois, USA

    Amanda L Marzo

  8. Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Paul G Thomas

  9. Department of Histology and Embryology, University of Rijeka School of Medicine, Rijeka, Croatia

    Biljana Zafirova & Bojan Polić

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  1. Andrew Zloza
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Contributions

A.Z., F.J.K. and J.A.G.-P. designed the study and wrote the manuscript; J.A.G.-P. supervised the project. G.E.L. generated the DNA constructs and performed WT CTL experiments. A.Z. performed the cytokine, kinetics, T-bet/JNK2, HIV and remainder of CTL experiments. J.M.S. designed the cytokine staining and JNK2 experiments. T.V.M., V.V., J.W.W. and A.Z. performed the influenza experiments. F.J.K., A.T.L., J.A.O., M.C.J., E.C.B., A.Z. and J.A.G.-P. performed DNA vaccinations and flow cytometric experiments. L.A.-H. collaborated on the HIV experiment; A.L.M., P.G.T. and A.I.S. collaborated on the influenza experiment. B.P. and B.Z. developed the NKG2D-deficient mice and collaborated on associated experiments. All authors edited the manuscript.

Corresponding author

Correspondence to José A Guevara-Patiño.

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Zloza, A., Kohlhapp, F., Lyons, G. et al. NKG2D signaling on CD8+ T cells represses T-bet and rescues CD4-unhelped CD8+ T cell memory recall but not effector responses. Nat Med 18, 422–428 (2012). https://doi.org/10.1038/nm.2683

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