OX40 Controls Functionally Different T Cell Subsets and Their Resistance to Depletion Therapy

Kroemer, Alexander; Xiang, Xiao; Vu, Minh Diem; Gao, Wenda; Minamimura, Keisuke; Chen, Ming; Maki, Takashi; Li, Xian Chang

doi:10.4049/jimmunol.179.8.5584

Cited by 62 publications

(55 citation statements)

References 33 publications

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“…20,22 Consistent with this idea, we could observe that CRC patients previously treated with neoadjuvant chemotherapy showed higher frequencies of total Tregs and especially of OX40 C Tregs, but not of OX40 C Tconvs, compared to matched controls for tumor stage and location (Fig. S3).…”

Section: Not Only Of Cd8supporting

confidence: 73%

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

et al. 2016

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Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor. Ex vivo, those Tregs suppressed the proliferation of tumorinfiltrating CD8C and CD4 C T cells. A differential compartmentalization was detected between Helios high and Helios low Treg subsets (thymus-derived versus peripherally induced): while Helios low Tregs were enriched in both sites, only Helios high Tregs accumulated significantly and specifically in tumors, displayed a highly demethylated TSDR region and contained high proportions of cells expressing CD39 and OX40, markers of activation and suppression. Besides the suppression of T cells, Tregs may contribute to CRC progression also through releasing IL-17, or differentiating into Tfr cells that potentially antagonize a protective Tfh response, events that were both detected in tumor-associated Tregs. Overall, our data indicate that Treg accumulation may contribute through multiple mechanisms to CRC establishment and progression.

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Section: Not Only Of Cd8supporting

confidence: 73%

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

et al. 2016

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“…Ϫ/Ϫ foxp3gfp mice and OX40Ltg-foxp3gfp mice were generated by crossing foxp3gfp mice with OX40 Ϫ/Ϫ mice or OX40Ltg mice and selected by PCR-based genotyping (26). Both Wt and OX40Ltg-foxp3gfp mice were also crossed with the congenic CD45.1 mice.…”

Section: Animalsmentioning

confidence: 99%

“…All TaqMan primers and probes were purchased from Applied Biosystems. Transcript levels of target genes were calculated according to the 2 Ϫ⌬⌬Ct method as supplied by the manufacturer (ABI PRISM 7700 user bulletin; Applied Biosystems) and expressed as arbitrary units (26).…”

Section: Real-time Pcrmentioning

confidence: 99%

OX40/OX40L Costimulation Affects Induction of Foxp3+ Regulatory T Cells in Part by Expanding Memory T Cells In Vivo

Xiang

Kroemer

Gao

et al. 2008

The Journal of Immunology

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OX40 is a member of the TNFR superfamily and has potent T cell costimulatory activities. OX40 also inhibits the induction of Foxp3+ regulatory T cells (Tregs) from T effector cells, but the precise mechanism of such inhibition remains unknown. In the present study, we found that CD4+ T effector cells from OX40 ligand-transgenic (OX40Ltg) mice are highly resistant to TGF-β mediated induction of Foxp3+ Tregs, whereas wild-type B6 and OX40 knockout CD4+ T effector cells can be readily converted to Foxp3+ T cells. We also found that CD4+ T effector cells from OX40Ltg mice are heterogeneous and contain a large population of CD44highCD62L− memory T cells. Analysis of purified OX40Ltg naive and memory CD4+ T effector cells showed that memory CD4+ T cells not only resist the induction of Foxp3+ T cells but also actively suppress the conversion of naive CD4+ T effector cells to Foxp3+ Tregs. This suppression is mediated by the production of IFN-γ by memory T cells but not by cell-cell contact and also involves the induction of T-bet. Importantly, memory CD4+ T cells have a broad impact on the induction of Foxp3+ Tregs regardless of their origins and Ag specificities. Our data suggest that one of the mechanisms by which OX40 inhibits the induction of Foxp3+ Tregs is by inducing memory T cells in vivo. This finding may have important clinical implications in tolerance induction to transplanted tissues.

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“…Real-time RT-PCR was performed as previously reported (21). In brief, total cellular RNA was extracted using the RNeasy Mini Kit (Qiagen) and reverse transcribed into cDNA with ABI Prism TaqMan reverse transcription method.…”

Section: Real-time Pcrmentioning

confidence: 99%

The Innate NK Cells, Allograft Rejection, and a Key Role for IL-15

Kroemer

Xiang

Degauque

et al. 2008

The Journal of Immunology

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116

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Transplant rejection is mediated primarily by adaptive immune cells such as T cells and B cells. The T and B cells are also responsible for the specificity and memory of the rejection response. However, destruction of allografts involves many other cell types including cells in the innate immune system. As the innate immune cells do not express germline-encoded cell surface receptors that directly recognize foreign Ags, these cells are thought to be recruited by T cells to participate in the rejection response. In this study, we examined the alloreactivity of the innate NK cells in Rag−/− mice using a stringent skin transplant model and found that NK cells at a resting state readily reject allogeneic cells, but not the skin allografts. We also found that IL-15, when preconjugated to its high affinity IL-15Rα-chain, is remarkably potent in stimulating NK cells in vivo, and NK cells stimulated by IL-15 express an activated phenotype and are surprisingly potent in mediating acute skin allograft rejection in the absence of any adaptive immune cells. Furthermore, NK cell-mediated graft rejection does not show features of memory responses. Our data demonstrate that NK cells are potent alloreactive cells when fully activated and differentiated under certain conditions. This finding may have important clinical implications in models of transplantation and autoimmunity.

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OX40 Controls Functionally Different T Cell Subsets and Their Resistance to Depletion Therapy

Cited by 62 publications

References 33 publications

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

OX40/OX40L Costimulation Affects Induction of Foxp3+ Regulatory T Cells in Part by Expanding Memory T Cells In Vivo

The Innate NK Cells, Allograft Rejection, and a Key Role for IL-15

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