B7H1-Ig fusion protein activates the CD4+ IFN-γ receptor+ type 1 T regulatory subset through IFN-γ-secreting Th1 cells

Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
The Journal of Immunology (Impact Factor: 4.92). 10/2006; 177(6):3606-14. DOI: 10.4049/jimmunol.177.6.3606
Source: PubMed


It has been demonstrated in our previous work that, in the human skin-grafting model, the expression of costimulatory molecule B7H1 (PD-L1) by keratinocytes plays an essential role in inducing local tolerance via activation of IL-10-secreting T cells. This study further analyzes the role of B7H1 in differentiation of type 1 T regulatory (Tr1) cells and explores underlying mechanisms. Mouse fusion protein B7H1-Ig is used, together with immobilized anti-CD3 mAb, to costimulate the purified naive CD4+ T cells. B7H1-Ig-treated CD4+ T cells were found to activate a characteristic Tr1 population possessing a CD4+ CD25- Foxp3- CD45RBlow phenotype. These regulatory T cells strongly inhibited the Th1-dominated MLR by secretion of IL-10 and TGF-beta. Moreover, B7H1-treated Tr1 cells also resulted in suppressed clinical scores and demyelination when adoptively transferred into mice with experimental allergic encephalomyelitis. Furthermore, analysis of the cytokine profile indicated that there were two differential reaction patterns during the B7H1-Ig-induced Tr1 development. These two patterns were characterized by activation of IFN-gammaR+ IL-10R- Th1 and IFN-gammaR+ IL-10R+ Tr1 cells, respectively. Secretion of IFN-gamma by Th1 and the expression of IFN-gammaR on Tr1 were critical for further Tr1 differentiation, as demonstrated by mAb blocking and by analysis in IFN-gamma(-/-) mice. In conclusion, B7H1 is capable of inducing Tr1 differentiation from naive CD4+ T cells by coactivation in an IFN-gamma- or Th1-dependent manner. Our study may shed some light upon the clinical usage of B7H1 as a therapeutic reagent for induction of tolerance.

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Available from: Lijun Xin, Oct 21, 2014
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    • "There is increasing evidence that Treg function could be influenced by Th1 cytokines, other that IL-2. Activated Treg express ifngr (20) and the receptor for IL-12p70 (il-12rβ2) (21). IL-12Rβ2−/− mice develop more rapid and severe autoimmune disease than wild-type (22) due to reduced CD4+CD25+ Treg activity (21). "
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    Frontiers in Immunology 05/2014; 5:190. DOI:10.3389/fimmu.2014.00190
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    • "Moreover a recent study by Koch et al. showed, that in a type 1 inflammation environment, IFNγ stimulated the differentiation of a specific subset of Tregs, which was able to migrate to the inflammatory site and exert antiinflammatory effects, optimized for the suppression of Th1 responses [46]. Furthermore, IFNγ produced by Th1 cells is able to stimulate a type I regulatory cells (Tr1) response, characterized by CD4+IL10 producing T cells [47]. The inflammatory response to myocarditis is characterized by a Th1-type immune response, therefore it is possible that the upregulation of IFNγ after MSC-injection was important for the activation of naïve and Tr1 regulatory T cells [36]. "
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    • "Generation of human IL-10–secreting Th1 cells was not affected by blocking antibodies against IFN-γ (Windhagen et al., 1996). Conversely, anti–IFN-γ suppressed the generation of IL-10 T reg cells after stimulation with a B7H1-Ig fusion protein (Ding et al., 2006). Furthermore, Shaw et al. (2006) proposed a model in which IFN-γ secretion by Th1 cells promotes IL-10 production among neighboring T cells by up-regulating ICOS-L expression on APCs. "
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