As described above, the investigation of the suppressive mechanism by Tregs showed that T cell suppression was mediated in a cell-contact-dependent manner. However, it was unclear whether this cell contact involved interac-tionsbetween TregsAPCorbetweenTregs andresponder Tcells. Inanelegant study Piccirillo and Shevach demonstrated that CD4+CD25+ Tregs that were preactivated anti-with CD3 mAb and APC could suppress CD8+ T cell proliferation and IFN-y production in response to stimulation with MHC class I/peptide tetramers in the absence of APCs . This paper provided direct evidence that CD4+CD25+ Tregs can suppress T cells in the absence of APCs. Nevertheless, this finding did not exclude the possibility that CD4+CD25+ Tregs can exert direct suppressive effects on APCs. Evidence that this might be the case is indeed accumulating. First of all, it has been demonstrated that CD4+CD25+ Tregs require antigen-specific activation before they can exert their suppressive effects [51, 83]. This indicates that CD4+CD25+ Tregs communicate with APCs in vivo through T cell receptor :MHC interactions, raising the possibility that CD4+CD25+ Tregs can influence the APCs. We and others have published previously that anergic/suppressive CD4+ T cells have the ability to suppress the T cell-stimulatory capacity of APCs. These APCs were either spleen-derived B cells and macrophages in Lewis rats  or dendritic cells in mice . In these studies, in vitro induced anergic/suppressive T cell clones were used; however, recent studies indicate that also the naturally occurring CD4+CD25+ regulatory T cells can affect the antigen-presenting function of APCs. Cederbom et al. described that CD4+CD25+ Tregs down-modulate CD80 and CD86 on bone marrow-derived DCs in mice, and that this had functional consequences since these DCs were poor inducers of naive T cell proliferation . Using human DCs, Misra et al. showed that upon co-culture with prestimulated CD4+CD25+ Tregs, the expression levels of CD40 and HLA-DR on DCs were reduced and that the percentages of CD86+ and CD83+ DC were decreased relative to untreated DCs . This altered pheno-
type was associated with a reduction in the T cell-stimulatory capacity during subsequent allogeneic and PPD-specific T cell stimulation assays, even when the DCs were incubated with rhCD40L prior to incubation with CD4+CD25+ Tregs. The modulatory effect was cell-contact-dependent since virtually no changes in DC phenotype were observed when cells were separated in a tran-swell system, although some role for IL-10 and TGF-3 was suggested. We have found similar data on the capacity of naturally occurring CD4+ CD25+ Tregs to inhibit the activation and function of human monocytes/macrophages (Taams et al., in press). CD14+ monocytes that were cultured with CD4+CD25+ Tregs displayed lower levels of CD86, and limited up-regulation of MHC class II, CD40 and CD80 relative to monocytes that were precultured without T cells or with CD4+CD25- T cells. These Treg-treated monocytes were strongly inhibited in their capacity to produce pro-inflammatory cytokines in response to LPS, and displayed a reduced T cell-stimulatory capacity compared to control monocytes.
Importantly, the regulation of APC function by CD4+CD25+ Tregs might also occur in vivo. It was shown recently that transfer of antigen-pulsed mature DCs into mice that were depleted for CD4+CD25+ Tregs resulted in higher Th1 responses compared to nondepleted mice . A different study by Maloy et al. using a T cell-independent mouse model for intestinal inflammation demonstrated that transfer of CD4+CD25+ Tregs resulted in reduced activation and recruitment of neutrophils, monocytes/macrophages, DCs and NK cells, which was partly mediated by IL-10 and TGF-3 . Together these data indicate that both the adaptive and the innate immune system are subject to CD4+CD25+ Treg-mediated suppression. The ability of Tregs to inhibit the function of many different cell types helps to explain the observations that CD4+CD25+ Tregs are efficient in suppressing many immune-mediated diseases including autoimmunity [12, 90, 91], transplant rejection , tumor immunity [93-95], allergy  and infection [38,97].
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