Role of TLRs in the induction of tolerogenic CD8a- dendritic cells by GM-CSF (50.34)

Abstract GM-CSF is a potent dendritic cell (DC) growth factor that plays an essential role in DC differentiation. We examined the potential of GM-CSF to impart tolerogenic potential to CD8a+ and CD8a- sub-populations of DCs. We show that GM-CSF selectively modulates myeloid CD8a-, and not plasmacytoid or CD8a+, DCs in vivo. GM-CSF treatment rendered CD8a- DCs tolerogenic which was characterized by the diminished production of inflammatory cytokines IL-12 and IL1β by these DCs. Self antigen, mouse thyroglobulin (mTg), presentation by GM-CSF exposed CD8a- DCs, relative to control CD8a- or other DCs, caused a significant increase in the frequency of Foxp3+ T cells among CD4+ T cells from mTg-primed mice. The ability of GM-CD8a- DCs to induce Foxp3+ T cells was severely abrogated upon addition of IL-12, and not IL1β, into the culture and indicated that reduced IL-12 production rendered them tolerogenic. Further, we studied the effects of treatment with various TLR ligands to either augment or abolish the effects of GM-CSF on CD8a- DCs. Interestingly, addition of TLR ligands such as LPS and CpG further augmented the ability of GM-CSF exposed CD8a- DCs to induce Foxp3+Tregs. These results indicated that exposure of GM-CD8a- DCs to TLR4 and TLR9 ligands can enhance their tolerogenic potential and strongly suggested that pro-inflammatory immune stimuli may confer an enhanced antigen specific tolerogenic effect on GM-CSF exposed CD8a- DCs. NIH 1RO1AI058190