NKG2D signaling shifts the balance of CD8 T cells from single cytokine- to polycytokine-producing effector cells

Frederick J. Kohlhapp; Jeremy A. O'Sullivan; Tamson V. Moore; Andrew Zloza; José A. Guevara-Patiño

doi:10.1016/j.molimm.2022.12.013

NKG2D signaling shifts the balance of CD8 T cells from single cytokine- to polycytokine-producing effector cells

Frederick J. Kohlhapp, Jeremy A. O'Sullivan, Tamson V. Moore, Andrew Zloza^*, José A. Guevara-Patiño^*

^*Corresponding author for this work

Medicine, Allergy Division

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

6 Scopus citations

Abstract

CD8 T cells play a critical role in immunity against intracellular pathogens and cancer. A primary objective of T cell-based vaccine strategies is the induction of durable and effective immune responses. Achieving this goal involves more than simply boosting the numbers of responding T cells. Of particular interest is the induction of CD8 T cells with polycytokine capability, specifically with the ability of CD8 T cells to co-produce IFNγ, TNFα and IL-2. The presence of these polycytokine-producing CD8 T cells correlates strongly with protection against foreign pathogens and cancer. Therefore, approaches capable of inducing such polyfunctional responses are needed. NKG2D engagement on CD8 T cells has been shown to result in increased effector response. However, the manner in which NKG2D engagement results in improved CD8 T cell effector response is unclear. Here we demonstrate in vitro and in vivo that NKG2D engagement by its natural ligand, Rae-1ε, shifts the balance from single cytokine to polycytokine (IL-2, IFNγ, and TFNα) production. These data define a previously unrecognized process in which NKG2D costimulation on CD8 T cells results in improved effector responses.

Original language	English (US)
Pages (from-to)	1-6
Number of pages	6
Journal	Molecular Immunology
Volume	155
DOIs	https://doi.org/10.1016/j.molimm.2022.12.013
State	Published - Mar 2023

Funding

For their kind gifts, we thank: Alan Houghton (pCRAN vector and OVA DNA; Memorial Sloan-Kettering Cancer Center, NY) and Lewis Lanier (Rae-1ε gene; UCSF, CA). This work was supported by the American Cancer Society , USA ( ACSLIB112496-RSG , to J.A.G.), American Cancer Society–Illinois Division , USA (Young Investigator Award Grant #07-20 , to J.A.G.), the National Institutes of Health , USA ( R21CA127037-01A1 to J.A.G.), Cancer Research Foundation (Young Investigator Award, to J.A.G.), R01 CA250514-05 to J.A.G. and the National Institutes of Health , USA (T32 Immunology Training Grant, The University of Chicago, AI07090 to A.Z., F.J.K., and J.A.O.). Volo Family Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. For their kind gifts, we thank: Alan Houghton (pCRAN vector and OVA DNA; Memorial Sloan-Kettering Cancer Center, NY) and Lewis Lanier (Rae-1ε gene; UCSF, CA). This work was supported by the American Cancer Society, USA (ACSLIB112496-RSG, to J.A.G.), American Cancer Society–Illinois Division, USA (Young Investigator Award Grant #07-20, to J.A.G.), the National Institutes of Health, USA (R21CA127037-01A1 to J.A.G.), Cancer Research Foundation (Young Investigator Award, to J.A.G.), R01 CA250514-05 to J.A.G. and the National Institutes of Health, USA (T32 Immunology Training Grant, The University of Chicago, AI07090 to A.Z. F.J.K. and J.A.O.). Volo Family Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study.

Keywords

CD8 T cells
Effector function
NKG2D
Polycytokine

ASJC Scopus subject areas

Molecular Biology
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.molimm.2022.12.013

Cite this

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title = "NKG2D signaling shifts the balance of CD8 T cells from single cytokine- to polycytokine-producing effector cells",

abstract = "CD8 T cells play a critical role in immunity against intracellular pathogens and cancer. A primary objective of T cell-based vaccine strategies is the induction of durable and effective immune responses. Achieving this goal involves more than simply boosting the numbers of responding T cells. Of particular interest is the induction of CD8 T cells with polycytokine capability, specifically with the ability of CD8 T cells to co-produce IFNγ, TNFα and IL-2. The presence of these polycytokine-producing CD8 T cells correlates strongly with protection against foreign pathogens and cancer. Therefore, approaches capable of inducing such polyfunctional responses are needed. NKG2D engagement on CD8 T cells has been shown to result in increased effector response. However, the manner in which NKG2D engagement results in improved CD8 T cell effector response is unclear. Here we demonstrate in vitro and in vivo that NKG2D engagement by its natural ligand, Rae-1ε, shifts the balance from single cytokine to polycytokine (IL-2, IFNγ, and TFNα) production. These data define a previously unrecognized process in which NKG2D costimulation on CD8 T cells results in improved effector responses.",

keywords = "CD8 T cells, Effector function, NKG2D, Polycytokine",

author = "Kohlhapp, {Frederick J.} and O'Sullivan, {Jeremy A.} and Moore, {Tamson V.} and Andrew Zloza and Guevara-Pati{\~n}o, {Jos{\'e} A.}",

note = "Funding Information: For their kind gifts, we thank: Alan Houghton (pCRAN vector and OVA DNA; Memorial Sloan-Kettering Cancer Center, NY) and Lewis Lanier (Rae-1ε gene; UCSF, CA). This work was supported by the American Cancer Society , USA ( ACSLIB112496-RSG , to J.A.G.), American Cancer Society–Illinois Division , USA (Young Investigator Award Grant #07-20 , to J.A.G.), the National Institutes of Health , USA ( R21CA127037-01A1 to J.A.G.), Cancer Research Foundation (Young Investigator Award, to J.A.G.), R01 CA250514-05 to J.A.G. and the National Institutes of Health , USA (T32 Immunology Training Grant, The University of Chicago, AI07090 to A.Z., F.J.K., and J.A.O.). Volo Family Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. Funding Information: For their kind gifts, we thank: Alan Houghton (pCRAN vector and OVA DNA; Memorial Sloan-Kettering Cancer Center, NY) and Lewis Lanier (Rae-1ε gene; UCSF, CA). This work was supported by the American Cancer Society, USA (ACSLIB112496-RSG, to J.A.G.), American Cancer Society–Illinois Division, USA (Young Investigator Award Grant #07-20, to J.A.G.), the National Institutes of Health, USA (R21CA127037-01A1 to J.A.G.), Cancer Research Foundation (Young Investigator Award, to J.A.G.), R01 CA250514-05 to J.A.G. and the National Institutes of Health, USA (T32 Immunology Training Grant, The University of Chicago, AI07090 to A.Z. F.J.K. and J.A.O.). Volo Family Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = mar,

doi = "10.1016/j.molimm.2022.12.013",

language = "English (US)",

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AU - Kohlhapp, Frederick J.

AU - O'Sullivan, Jeremy A.

AU - Moore, Tamson V.

AU - Zloza, Andrew

AU - Guevara-Patiño, José A.

N1 - Funding Information: For their kind gifts, we thank: Alan Houghton (pCRAN vector and OVA DNA; Memorial Sloan-Kettering Cancer Center, NY) and Lewis Lanier (Rae-1ε gene; UCSF, CA). This work was supported by the American Cancer Society , USA ( ACSLIB112496-RSG , to J.A.G.), American Cancer Society–Illinois Division , USA (Young Investigator Award Grant #07-20 , to J.A.G.), the National Institutes of Health , USA ( R21CA127037-01A1 to J.A.G.), Cancer Research Foundation (Young Investigator Award, to J.A.G.), R01 CA250514-05 to J.A.G. and the National Institutes of Health , USA (T32 Immunology Training Grant, The University of Chicago, AI07090 to A.Z., F.J.K., and J.A.O.). Volo Family Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. Funding Information: For their kind gifts, we thank: Alan Houghton (pCRAN vector and OVA DNA; Memorial Sloan-Kettering Cancer Center, NY) and Lewis Lanier (Rae-1ε gene; UCSF, CA). This work was supported by the American Cancer Society, USA (ACSLIB112496-RSG, to J.A.G.), American Cancer Society–Illinois Division, USA (Young Investigator Award Grant #07-20, to J.A.G.), the National Institutes of Health, USA (R21CA127037-01A1 to J.A.G.), Cancer Research Foundation (Young Investigator Award, to J.A.G.), R01 CA250514-05 to J.A.G. and the National Institutes of Health, USA (T32 Immunology Training Grant, The University of Chicago, AI07090 to A.Z. F.J.K. and J.A.O.). Volo Family Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. Publisher Copyright: © 2023

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N2 - CD8 T cells play a critical role in immunity against intracellular pathogens and cancer. A primary objective of T cell-based vaccine strategies is the induction of durable and effective immune responses. Achieving this goal involves more than simply boosting the numbers of responding T cells. Of particular interest is the induction of CD8 T cells with polycytokine capability, specifically with the ability of CD8 T cells to co-produce IFNγ, TNFα and IL-2. The presence of these polycytokine-producing CD8 T cells correlates strongly with protection against foreign pathogens and cancer. Therefore, approaches capable of inducing such polyfunctional responses are needed. NKG2D engagement on CD8 T cells has been shown to result in increased effector response. However, the manner in which NKG2D engagement results in improved CD8 T cell effector response is unclear. Here we demonstrate in vitro and in vivo that NKG2D engagement by its natural ligand, Rae-1ε, shifts the balance from single cytokine to polycytokine (IL-2, IFNγ, and TFNα) production. These data define a previously unrecognized process in which NKG2D costimulation on CD8 T cells results in improved effector responses.

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KW - Polycytokine

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NKG2D signaling shifts the balance of CD8 T cells from single cytokine- to polycytokine-producing effector cells

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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