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

doi:10.1038/nm.2683

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

Medicine, Allergy Division

Research output: Contribution to journal › Article › peer-review

52 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 language	English (US)
Pages (from-to)	422-428
Number of pages	7
Journal	Nature Medicine
Volume	18
Issue number	3
DOIs	https://doi.org/10.1038/nm.2683
State	Published - Mar 2012

Funding

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-1ε–expressing EL-4 cells; The University of Chicago); L. Lanier (genes encoding Rae-1ε, Rae-1ε–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 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.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Cite this

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

@article{3fda1489517c4d66bbb1e46153884c6a,

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-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.",

author = "Andrew Zloza and Kohlhapp, {Frederick J.} and Lyons, {Gretchen E.} and Schenkel, {Jason M.} and Moore, {Tamson V.} and Lacek, {Andrew T.} and O'Sullivan, {Jeremy A.} and Vineeth Varanasi and Williams, {Jesse W.} and Jagoda, {Michael C.} and Bellavance, {Emily C.} and Marzo, {Amanda L.} and Thomas, {Paul G.} and Biljana Zafirova and Bojan Poli{\'c} and Lena Al-Harthi and Sperling, {Anne I.} and Guevara-Pati{\~n}o, {Jos{\'e} A.}",

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.",

year = "2012",

month = mar,

doi = "10.1038/nm.2683",

language = "English (US)",

volume = "18",

pages = "422--428",

journal = "Nature Medicine",

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Zloza, A, Kohlhapp, FJ, Lyons, GE, Schenkel, JM, Moore, TV, Lacek, AT, O'Sullivan, JA, Varanasi, V, Williams, JW, Jagoda, MC, Bellavance, EC, Marzo, AL, Thomas, PG, Zafirova, B, Polić, B, Al-Harthi, L, Sperling, AI & Guevara-Patiño, JA 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, vol. 18, no. 3, pp. 422-428. https://doi.org/10.1038/nm.2683

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T1 - NKG2D signaling on CD8 + T cells represses T-bet and rescues CD4-unhelped CD8 + T cell memory recall but not effector responses

AU - Zloza, Andrew

AU - Kohlhapp, Frederick J.

AU - Lyons, Gretchen E.

AU - Schenkel, Jason M.

AU - Moore, Tamson V.

AU - Lacek, Andrew T.

AU - O'Sullivan, Jeremy A.

AU - Varanasi, Vineeth

AU - Williams, Jesse W.

AU - Jagoda, Michael C.

AU - Bellavance, Emily C.

AU - Marzo, Amanda L.

AU - Thomas, Paul G.

AU - Zafirova, Biljana

AU - Polić, Bojan

AU - Al-Harthi, Lena

AU - Sperling, Anne I.

AU - Guevara-Patiño, José A.

N1 - 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.

PY - 2012/3

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