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

• Published in: Molecular immunology 2023-03, Vol.155, p.1-6
• Main Authors: Kohlhapp, Frederick J., O’Sullivan, Jeremy A., Moore, Tamson V., Zloza, Andrew, Guevara-Patiño, José A.
• Format: Article
• Language: English
• Subjects: CD8 T cells; CD8-Positive T-Lymphocytes; Cytokines; Effector function; Humans; immunity; Interleukin-2; ligands; Neoplasms; NK Cell Lectin-Like Receptor Subfamily K; NKG2D; Polycytokine; vaccines
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2022.12.013

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. •NKG2D engagement of its natural ligand, Rae-1ε,•shifts the balance from single-cytokine to polycytokine (IL-2, IFNγ, and TFNα) production.•The generated NKG2D-induced polycytokine-producing CD8 + T cells also produce higher levels of cytokines on a per-cell basis.•To our knowledge this is the first experimental evidence supporting the role of NKG2D in dictating CD8 + T cell polycytokine responses.•These findings suggest that vaccination methods which co-deliver NKG2D ligands in addition to antigen may produce more effective future protection against pathogens and may provide key insight into how enduring therapeutic responses might be achieved in patients.