A new T‐cell activation mode for suboptimal doses of antigen under the full activation of T cells with different specificity

Shibuya, Masatoyo; Fujio, Keishi; Shoda, Hirofumi; Okamura, Tomohisa; Okamoto, Akiko; Sumitomo, Shuji; Yamamoto, Kazuhiko

doi:10.1002/eji.201444965

Cited by 5 publications

(2 citation statements)

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“…These findings seem to challenge the current view that pathogens have evolved mechanisms to inhibit immunogenic cell death so as to enhance their ability to persist and cause disease . However, this report suggests that c‐di‐AMP‐induced monocyte apoptosis might instead trigger an alternative type of immune response, possibly related to bystander activation rather than to “extended antigen priming” .…”

Section: Discussionmentioning

confidence: 55%

Cyclic dinucleotides modulate human T‐cell response through monocyte cell death

et al. 2015

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Cyclic dinucleotides, a class of microbial messengers, have been recently identified in bacteria, but their activity in humans remains largely unknown. Here, we have studied the function of cyclic dinucleotides in humans. We found that c-di-AMP and cGAMP, two adenosine-based cyclic dinucleotides, activated T lymphocytes in an unusual manner through monocyte cell death. c-di-AMP and cGAMP induced the selective apoptosis of human monocytes, and T lymphocytes were activated by the direct contact with these dying monocytes. The ensuing T-cell response comprised cell-cycle exit, phenotypic maturation into effector memory cells and proliferation arrest, but not cell death. This quiescence was transient since T cells remained fully responsive to further restimulation. Together, our results depict a novel activation pattern for human T lymphocytes: a transient quiescence induced by c-di-AMP-or cGAMP-primed apoptotic monocytes.Keywords: Activation r A2a adenosine receptor r Cyclic dinucleotides r Quiescence r T lymphocytes Additional supporting information may be found in the online version of this article at the publisher's web-site

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Section: Discussionmentioning

confidence: 55%

Cyclic dinucleotides modulate human T‐cell response through monocyte cell death

et al. 2015

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“…First, suboptimal T cell stimulation has been shown to contribute to persistent diseases, such as M. tuberculosis [20] or T. cruzi [21], so determination of the effects and mechanisms of CBD under low-level stimulation conditions will contribute to information on its putative therapeutic usefulness. Second, suboptimal T cell stimulation can be influenced by the presence of optimal stimulation of a distinct antigen, in what has been termed extended antigen priming [22], so studying low-level stimulation in the absence and presence of other antigens is key to understanding complex immune responses. Third, our previous study demonstrated that CBD either inhibited or enhanced IL-2 and IFN-γ production in response to optimal or suboptimal T cell activation, respectively [23], demonstrating that cellular activation dictates the CBD response.…”

Section: Introductionmentioning

confidence: 99%

Cannabidiol (CBD) induces functional Tregs in response to low-level T cell activation

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Park

Seo

et al. 2017

Cellular Immunology

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Many effects of the non-psychoactive cannabinoid, cannabidiol (CBD), have been described in immune responses induced by strong immunological stimuli. It has also been shown that CBD enhances IL-2 production in response to low-level T cell stimulation. Since IL-2, in combination with TGF-β1, are critical for Treg induction, we hypothesized that CBD would induce CD4+CD25+FOXP3+ Tregs in response to low-level stimulation. Low-level T cell stimulation conditions were established based on minimal CD25 expression in CD4+ cells using suboptimal PMA/Io (4 nM/0.05 μM, S/o), ultrasuboptimal PMA/Io (1 nM/0.0125 μM, Us/o) or soluble anti-CD3/28 (400-800 ng each, s3/28). CBD increased CD25+FOXP3+ cells from CD4+, CD4+CD25+, and CD4+CD25− T cells, as well as in CD4+ T cells derived from FOXP3-GFP mice. Most importantly, the Us/o + CBD-induced CD4+CD25+ Tregs robustly suppressed responder T cell proliferation, demonstrating that the mechanism by which CBD is immunosuppressive under low-level T cell stimulation involves induction of functional Tregs.

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