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

Zloza, Andrew; Kohlhapp, Frederick J.; Lyons, Gretchen E.; Schenkel, Jason M.; Moore, Tamson V.; Lacek, Andrew T.; O’Sullivan, Jeremy A.; Varanasi, Vineeth; Williams, Jesse W.; Jagoda, Michael C.; Bellavance, Emily; Marzo, Amanda L.; Thomas, Paul G.; Zafirova, Biljana; Polić, Bojan; Al‐Harthi, Lena; Sperling, Anne I.; Guevara-Patiño, José A.

doi:10.1038/nm.2683

Cited by 58 publications

(72 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, NKG2D-ligand overexpression was shown to improve effector functions of memory CD8 T cells in immune-deficient mice (9). In this study, we demonstrate that NKG2D also mediates memory cell formation.…”

Section: Discussionsupporting

confidence: 62%

“…Recently, it was shown that in the absence of CD4 T cell help, NKG2D hyperstimulation can affect expression of T-bet in CD8 T cells (9). Therefore, we investigated whether NKG2D only promotes survival or also gene transcription in our culture system.…”

Section: Nkg2d Promotes Survival Of Cd8 Memory Precursorsmentioning

confidence: 99%

“…More recently, NKG2D was implied in effector functions of memory CD8 T cells. In the absence of CD4 T cells, the presence of NKG2D ligands during priming rescued recall capabilities of memory CD8 T cells (9).…”

mentioning

confidence: 98%

See 2 more Smart Citations

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Wensveen

Lenartić

Jelenčić

et al. 2013

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Memory formation of activated CD8 T cells is the result of a specific combination of signals that promote long-term survival and inhibit differentiation into effector cells. Much is known about initial cues that drive memory formation, but it is poorly understood which signals are essential during the intermediate stages before terminal differentiation. NKG2D is an activating coreceptor on Ag-experienced CD8 T cells that promotes effector cell functions. Its role in memory formation is currently unknown. In this study, we show that NKG2D controls formation of CD8 memory T cells by promoting survival of precursor cells. We demonstrate that NKG2D enhances IL-15–mediated PI3K signaling of activated CD8 T cells, in a specific phase of memory cell commitment, after activation but before terminal differentiation. This signal is essential for the induction of prosurvival protein Mcl-1 and precursor cell survival. In vivo, NKG2D deficiency results in reduced memory cell formation and impaired protection against reinfection. Our findings show a new role for PI3K and the NKG2D/IL-15 axis in an underappreciated stage of effector to memory cell transition that is essential for the generation of antiviral immunity. Moreover, we provide novel insights how these receptors control both effector and memory T cell differentiation.

show abstract

Section: Discussionsupporting

confidence: 62%

Section: Nkg2d Promotes Survival Of Cd8 Memory Precursorsmentioning

confidence: 99%

See 1 more Smart Citation

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Wensveen

Lenartić

Jelenčić

et al. 2013

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…23 Unlike with NKG2D C NK and NK T cells, however, NKG2D expression rescues CD8 C T-cell memory in the absence of CD4 C T-cell assistance. 21 In a colon cancer model, NKG2D activation on the surface of intraepithelial lymphocytes induced Fas ligand production and cytotoxicity independent of TCR signaling, suggesting a particular characteristic of NKG2D on CD8 C intraepithelial lymphocytes. 6 In esophageal cancer patients, NKG2D expression was reduced on CD8 C T cells in those with advanced-stage disease, which is inversely correlated with the frequency of regulatory T cells.…”

Section: Discussionmentioning

confidence: 92%

“…However, the biology of NKG2D receptor was primarily determined via investigation of NK cells. Increasing evidence demonstrates that NKG2D C T cells enhance memory features, 21 defend against tumor cells and pathogens, 6,22,23 and balance the effective and regulatory characteristics of T cells, 24 suggesting a substantial role for NKG2D in cross-talk between innate and adaptive immune responses. Like NKG2D C NK and NK T cells, NKG2D C T cells eliminate bacterially infected NKG2D ligand C cells 22 as well as the JHM strain of mouse hepatitis virus in the central nervous system in mice with acute disease.…”

Section: Discussionmentioning

confidence: 99%

Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

Batth

Xia

et al. 2016

OncoImmunology

View full text Add to dashboard Cite

The natural killer (NK) group 2D (NKG2D) receptor, which displays on mouse and human NK cells, activates CD8 C T cells and small subsets of other T cells. NKG2D C CD8 C T cells play critical roles in both innate and adaptive immunity upon engagement with NKG2D ligands to eliminate tumor and infected cells. Despite the important role of NKG2D C CD8 C T cells in immune surveillance, the mechanisms of how NKG2D expression on CD8 C T cells is regulated remain poorly defined. We treated mouse and human CD8 C T cells with CD80 recombinant protein, plus a pharmacologic model with small molecular inhibitors to determine which signaling pathway leads to NKG2D regulation on CD8 C T cells. This study revealed that CD28 activation gives rise to sustained NKG2D expression on both mouse and human CD8 C T cells in a signal transducer and activator of transcription 3 (STAT3) phosphorylation-dependent manner. Further, we found that CD28 activation stimulated sustained activation of the tyrosine kinase Lck, which recruits and triggers Janus kinase/STAT3 signaling to phosphorylate STAT3, and in turn increases NKG2D expression. Moreover, NKG2D induction on CD8 C T cells exerts cytolytic activity against target tumor cells in vitro, as well as significantly improves the antitumor therapeutic effects in vivo in an NKG2D-dependent manner. Taken together, these results elucidated a novel mechanism of NKG2D regulation by phosphorylated STAT3 (pSTAT3) on CD8 C T cells upon CD28 activation. This mechanism may shed light on the effectiveness of CD80-based, NKG2D-dependent antitumor immunotherapy.

show abstract

NKG2D signaling in cancer immunosurveillance

López‐Soto

Huergo-Zapico

Acebes-Huerta

et al. 2014

Intl Journal of Cancer

119

View full text Add to dashboard Cite

The immune system is able to detect and eliminate transformed cells. The activating receptor NKG2D is particularly relevant for cancer immunosurveillance. NKG2D ligand expression renders tumor cells more susceptible to be killed by NK and T cells, and correlates with the clinical outcome of the disease. However, tumors develop mechanisms to overcome the NKG2D-mediated immune response, which has been associated with poor prognosis and impairment of the clinical benefits of immunotherapy in many human cancers. The highly specific pattern of expression displayed by the NKG2D ligands, mainly confined to tumor cells, together with the strong immune response triggered by this receptor clearly supports the idea that the NKG2D-mediated pathway may be a powerful target for the treatment of cancer. This review draws together the most recent discoveries concerning the biology of the NKG2D signaling and their therapeutic relevance in the context of cancer.

show abstract

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

Cited by 58 publications

References 56 publications

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

NKG2D signaling in cancer immunosurveillance

Contact Info

Product

Resources

About

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

Cited by 58 publications

References 56 publications

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Regulation of NKG2D+CD8+T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

NKG2D signaling in cancer immunosurveillance

Contact Info

Product

Resources

About

Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism