Activation of NF-κB1 by OX40 Contributes to Antigen-Driven T Cell Expansion and Survival

Song, Jianxun; So, Takanori; Croft, Michael

doi:10.4049/jimmunol.180.11.7240

Cited by 111 publications

(122 citation statements)

References 57 publications

(57 reference statements)

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…One of them, CD27, has been previously linked to Eomes expression (21). However, we observed that neither activation of CD27 nor OX40 signaling with agonist antibodies (22,23) altered Eomes expression in memory T cells (Fig. S1B).…”

Section: Significancecontrasting

confidence: 39%

“…To address this question, we altered NFκB signaling using gain and loss-offunction approaches in proliferating T cells. First, we transduced CD8 T cells with a construct that encodes constitutive active IKKβ (CA-IKKβ) to enhance NFκB signaling (22). CA-IKKβ GFP + -transduced cells exhibited lower levels of IκBα (as a consequence of increased proteosomal degradation) than their EV-transduced counterparts, confirming constitutive NFκB signaling (33).…”

Section: Significancementioning

confidence: 99%

“…TNFR family members can induce NFκB signaling (22,38). However, TNFR CD27, OX40, TRAIL, and 41BB (which have been linked to memory) were either not expressed at the contraction phase or did not have a role in regulating Eomes (Figs.…”

Section: Tcr-dependent Nfκb Signaling Is Required For Eomes Expressionmentioning

confidence: 99%

See 2 more Smart Citations

NFκB–Pim-1–Eomesodermin axis is critical for maintaining CD8 T-cell memory quality

Knudson

Pritzl

Saxena

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

T-cell memory is critical for long-term immunity. However, the factors involved in maintaining the persistence, function, and phenotype of the memory pool are undefined. Eomesodermin (Eomes) is required for the establishment of the memory pool. Here, we show that in T cells transitioning to memory, the expression of high levels of Eomes is not constitutive but rather requires a continuum of cell-intrinsic NFκB signaling. Failure to maintain NFκB signals after the peak of the response led to impaired Eomes expression and a defect in the maintenance of CD8 T-cell memory. Strikingly, we found that antigen receptor [T-cell receptor (TCR)] signaling regulates this process through expression of the NFκB-dependent kinase proviral integration site for Moloney murine leukemia virus-1 (PIM-1), which in turn regulates NFκB and Eomes. T cells defective in TCR-dependent NFκB signaling were impaired in late expression of Pim-1, Eomes, and CD8 memory. These defects were rescued when TCRdependent NFκB signaling was restored. We also found that NFκB-Pim-1 signals were required at memory to maintain memory CD8 T-cell longevity, effector function, and Eomes expression. Hence, an NFκB-Pim-1-Eomes axis regulates Eomes levels to maintain memory fitness.CD8 T-cell memory | NFkB | Pim-1 | Eomesodermin

show abstract

Section: Significancecontrasting

confidence: 39%

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

NFκB–Pim-1–Eomesodermin axis is critical for maintaining CD8 T-cell memory quality

Knudson

Pritzl

Saxena

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Furthermore, effective ΙΚΚβ expression alone is sufficient to restore the defective proliferation and survival of OX40-deficient T cells in vivo when responding to antigen. Thus, OX40 signals regulate T cell number and viability through the NF-κΒ1 pathway that controls the expression and activity of intracellular targets for proliferation and survival (32). Collectively, mediated by PI3K/PKB/NF-κB pathways, CD28 and OX40 regulate expression of bcl-2 family members and survivin/ aurora B that control T cell proliferation, cell cycle progression, and longevity (16,33).…”

Section: Common Pi3k/pkb/nf-κβ Pathwaysmentioning

confidence: 99%

Intracellular Signals of T Cell Costimulation

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…OX40 is a costimulatory molecule constitutively expressed by Treg cells and expressed upon activation by T effector (Teff) cells. Triggering of OX40 has opposite effects on these two T-cell populations: Treg cells are inhibited in their suppressive functions [3][4][5][6], while Teff cells are stimulated to proliferate, survive and gain memory phenotype [7][8][9][10][11]. Treatment of different types of mouse transplantable tumors with the mAb OX86, the agonist of OX40, favors tumor rejection thanks to its double effect on Treg and Teff cells [3,12].…”

Section: Introductionmentioning

confidence: 99%

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

et al. 2011

View full text Add to dashboard Cite

Treg cells maintain the tumor microenvironment in an immunosuppressive state preventing an effective anti-tumor immune response. A possible strategy to overcome Treg-cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while being induced in activated effector T cells. OX40 stimulation, by the agonist mAb OX86, inhibits Treg-cell suppression and boosts effector T-cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, the most abundant CD4 1 populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor interferon regulatory factor 1 (IRF1). Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to DCs. The CD40L/CD40 axis was required for Tem-cellmediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg-cell suppression and enhancement of the Tem-cell adjuvant effect both concurred to free DCs from immunosuppression and activate the immune response against the tumor. 3615The tumor microenvironment is characterized by an immunosuppressive cytokine milieu, which promotes immune tolerance and tumor growth. Treg cells secrete interleukin 10 (IL-10), which plays a critical role in suppressing immune responses and in particular the maturation of fully competent DCs [13][14][15]. Among tumor-infiltrating Teff cells, the subpopulation of effector memory T (Tem) cells is the most abundant. Tem cells are CD4 1 CD44 high CD62L low lymphocytes excluded from resting lymph nodes and mainly localized in peripheral tissues; upon stimulation they rapidly activate and secrete effector cytokines like IFN-g, but they have limited proliferative capacity [16]. In experimental models of immune activation, Tem cells constitutively express CD40L at levels sufficient to induce DC activation in an antigen-independent manner [17]. The CD40/CD40L axis is crucial for DC maturation and the subsequent T-cell priming. However in the tumor microenvironment this costimulatory pathway is often dampened, thus impairing the generation of an efficient anti-tumor immune response [18,19].In this study we have investigated the mechanisms by which OX86 modulates Treg-and Teff-cell functions and their reciprocal interactions with DCs at the tumor site. We propose a model of the tumor microenvironment in which, after OX86 treatment, DCs receive a lower IL-10-mediated inhibition by Treg cells on the one hand, and a stronger stimulation from Tem cells, via the CD40/CD40L axis, on the other. In this favorable condition, DCs acquire a stronger migratory ability toward the draining LNs (dLNs), thus inducing a specific anti-tumor immune response. ResultsIntratumoral ...

show abstract

Activation of NF-κB1 by OX40 Contributes to Antigen-Driven T Cell Expansion and Survival

Cited by 111 publications

References 57 publications

NFκB–Pim-1–Eomesodermin axis is critical for maintaining CD8 T-cell memory quality

NFκB–Pim-1–Eomesodermin axis is critical for maintaining CD8 T-cell memory quality

Intracellular Signals of T Cell Costimulation

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

Contact Info

Product

Resources

About