Interestingly, CD8α+ DC can produce large amounts of TGF-β 14. This finding may explain their ability to induce Th17 responses in an inflammatory setting and fits with our previous finding of TGF-β-dependent induction of Th17

cells by curdlan-stimulated DC in vitro25. In addition, TGF-β acts to promote the conversion of naïve T cells into antigen-specific Treg in non-inflammatory conditions 14, 30, 31. This can be seen with small amounts of DNGR-1-targeted antigen in the absence of adjuvant, in agreement with previous conclusions that antigen presentation in sub-immunogenic conditions promotes establishment of tolerance 12. Notably, the CD8α+ NVP-AUY922 datasheet DC population includes cells able to synthesize retinoic acid, which enhances selleck kinase inhibitor Treg conversion 32. It is intriguing to speculate that such cells might be responsible for Treg conversion following antigen targeting to DNGR-1. The fact that high doses of antigen and/or strong activation of DC limit Treg accumulation can be explained by the antagonistic effect of T-cell proliferation on the Treg conversion process, as previously reported by Kretschmer et al. upon antigen delivery using anti-DEC205 mAb 12. Tolerance induction by antigen targeting to DNGR-1 could be useful in clinical settings for inducing transplantation

tolerance or controlling autoimmunity and could be improved, for example, by co-administering immunomodulatory molecules, TCL such as IL-2 and rapamycin, which expand freshly generated Treg while selectively dampening down the “effector” population 33. It is worth noting that in contrast to the induction of Th1, Th17 or Foxp3+ cells, we cannot induce the differentiation of Th2 cells. This result is in line with the notion that CD8α+ DC are poor Th2 inducers 34 and fits with recent publications showing that antigen presentation by DC is not involved in driving Th2 responses 35–37. Thus, vaccines or immunotherapies employing antigen targeting to DNGR-1 are unlikely to inadvertently drive a detrimental allergic Th2 response. We can promote Th1 differentiation with

CpG and anti-CD40 mAb but find that poly I:C is by far the most potent inducer of Th1 priming, in agreement with a recent publication 23. Notably, double-stranded RNA, such as poly I:C, triggers IL-12 production in DC 38, but it has been reported that IL-12 is dispensable for Th1 priming when antigen is selectively targeted to CD8α+ DC 10. Our finding that anti-DNGR-1 conjugates plus poly I:C prime normal Th1 responses in IL-12 p40-deficient animals is consistent with that report. Antigen targeting to some DC-expressed C-type lectin receptor has been reported to trigger CD4+ T-cell help-dependent B-cell responses in the absence of adjuvant 39, 40. In line with these observations, Caminschi et al.