Gap junctions between regulatory T cells and dendritic cells prevent sensitization of CD8+ T cells

Contact hypersensitivity (CHS) of murine skin serves as a model of allergic contact dermatitis. Hapten-specific CD8 T cells and neutrophils represent the major effector cells driving this inflammatory reaction whereas Foxp3+ regulatory T cells (Tregs) control the severity of inflammation. However, whether in vivo expansion of endogenous Tregs can downregulate CHS-mediated inflammation remains to be elucidated. In this study, we addressed this issue by using injection of an IL-2/anti–IL-2 mAb JES6-1 complex (IL-2/JES6-1) as a means of Treg induction in 2,4,6-trinitrochlorobenzene–induced CHS. IL-2/JES6-1 injection before or after hapten sensitization led to a considerable reduction of skin inflammation, even when rechallenged up to 3 wk after the last treatment. Conversely, Treg depletion re-established the CHS response in IL-2/JES6-1–treated mice. IL-2/JES6-1 injection resulted in increased frequencies of natural and peripheral Tregs in spleen and draining lymph nodes (LNs), elevated IL-10 and TGF-β production by CD4 T cells, reduced CD86 expression by dendritic cells, and led to lower numbers of hapten-specific IFN-γ–producing CD8 T effector cells in LNs. Neutrophil and CD8 T cell infiltration was reduced in inflamed ear tissue, whereas CTLA-4+Foxp3+ Treg frequencies were augmented. Adoptive transfer of LN cells of sensitized mice into recipients treated with IL-2/JES6-1 showed impaired CHS. Our results show that in vivo Treg expansion results in a prolonged CHS suppression, a sustained reduction of hapten-specific CD8 T cells, and a decrease in effector cell influx in inflamed tissue.

mentioning

confidence: 99%

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

Beidaq

Link

Hofmann

et al. 2016

“…Dendritic cells (DCs) are the most potent APCs of our immune system and have been shown to take center stage in the interplay among DCs, T regs , and CD8 + T cells (19)(20)(21). In cancer, they are critically important for activating CD8 + T cells into potent cytotoxic T cells capable of lysing tumor cells (22,23).…”

mentioning

confidence: 99%

Modulation of Regulatory T Cell Function by Monocyte-Derived Dendritic Cells Matured through Electroporation with mRNA Encoding CD40 Ligand, Constitutively Active TLR4, and CD70

Pen

Keersmaecker

Maenhout

et al. 2013

Regulatory T cells (Tregs) counteract anticancer immune responses through a number of mechanisms, limiting dendritic cell (DC)–based anticancer immunotherapy. In this study, we investigated the influence of various DC activation stimuli on the Treg functionality. We compared DCs activated by electroporation with mRNA encoding constitutively active TLR4 (caTLR4) and CD40 ligand (DiMix-DCs), or these factors together with mRNA encoding the costimulatory molecule CD70 (TriMix-DCs) with DCs maturated in the presence of a mixture of inflammatory cytokines (DCs maturated with a combination of the cytokines IL-1β, IL-6, TNF-α, and PGE2) for their ability to counteract Tregs on different levels. We first demonstrated that there was no difference in the extent of Treg induction starting from CD4+CD25− T cells under the influence of the different DC maturation stimuli. Second, we showed that both DiMix- and TriMix-DCs could partly alleviate Treg inhibition of CD8+ T cells. Third, we observed that CD8+ T cells that had been precultured with DiMix-DCs or TriMix-DCs were partially protected against subsequent Treg suppression. Finally, we showed that Tregs cocultured in the presence of TriMix-DCs, but not DiMix-DCs, partially lost their suppressive capacity. This was accompanied by a decrease in CD27 and CD25 expression on Tregs, as well as an increase in the expression of T-bet and secretion of IFN-γ, TNF-α, and IL-10, suggesting a shift of the Treg phenotype toward a Th1 phenotype. In conclusion, these data suggest that TriMix-DCs are not only able to suppress Treg functions, but moreover could be able to reprogram Tregs to Th1 cells under certain circumstances.

“…For instance, we and others have shown that Treg are able to interconnect with DC via gap junctions (4,5). After contact to Treg, DC produced reduced amounts of IL-1b and TNF-a, whereas the immunomodulatory cytokine IL-10 was upregulated.…”

mentioning

confidence: 87%

Regulatory T Cell–Derived Adenosine Induces Dendritic Cell Migration through the Epac-Rap1 Pathway

Ring

Pushkarevskaya

Schild

et al. 2015

Self Cite

Dendritic cells (DC) are one target for immune suppression by regulatory T cells (Treg), because their interaction results in reduced T cell stimulatory capacity and secretion of inhibitory cytokines in DC. We show that DC in the presence of Treg are more mobile as compared with cocultures with conventional CD4+ T cells and form DC–Treg aggregates within 2 h of culture. The migration of DC was specifically directed toward Treg, as Treg, but not CD4+ T cells, attracted DC in Boyden chambers. Treg deficient for the ectonucleotidase CD39 were unable to attract DC. Likewise, addition of antagonists for A2A adenosine receptors abolished the formation of DC–Treg clusters, indicating a role for adenosine in guiding DC–Treg interactions. Analysis of the signal transduction events in DC after contact to Treg revealed increased levels of cAMP, followed by activation of Epac1 and the GTPase Rap1. Subsequently activated Rap1 localized to the subcortical actin cytoskeleton in DC, providing a means by which directed locomotion of DC toward Treg is facilitated. In aggregate, these data show that Treg degrade ATP to adenosine via CD39, attracting DC by activating Epac1-Rap1–dependent pathways. As a consequence, DC–Treg clusters are formed and DC are rendered less stimulatory. This adenosine-mediated attraction of DC may therefore act as one mechanism by which Treg regulate the induction of immune responses by DC.