Tumor-mediated down-regulation of MHC class II in DC development is attributable to the epigenetic control of the CIITA type I promoter

Young-Eun Choi, Ha-Nul Yu, Cheol-Hee Yoon, Yong-Soo Bae
European Journal of Immunology 2009, 39 (3): 858-68
In patients with cancer, DC express significantly lower amounts of MHC class II compared with those of normal individuals. However, the underlying mechanisms for this have not yet been fully defined. In the present study, we found that IL-10 plays a major role in the tumor-conditioned medium (TCM)-mediated decrease of MHC class II expression on BM-derived DC. IL-10 inhibited the expression of type I CIITA during DC differentiation. GM-CSF-mediated histone (H3 and H4) acetylation at the type I promoter (pI) locus of the CIITA gene was markedly increased during DC differentiation and this increase was blocked by IL-10. We also found that STAT5 bound to the CIITA pI locus during DC differentiation, and the binding was markedly attenuated by TCM or IL-10. Altogether, these findings suggest that (i) the down-regulation of MHC class II in tumor microenvironments is most likely attributable to IL-10 in the TCM and (ii) IL-10-mediated MHC class II down-regulation results from the inhibition of type I CIITA expression. This inhibition is most likely due to blocking of the STAT5-associated epigenetic modifications of the CIITA pI locus during the entire period of DC differentiation from BM cells, as opposed to a simple inhibition of MHC class II expression at the DC stage.

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