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

Abstract

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.

Bare lymphocyte syndrome: An opportunity to discover our immune system

“…Similarly, squamous cell carcinoma in a TAP2 deficient patient has raised a serious question about the risk linked to MHC deficiency [40]. Although it was in contradiction to the observation made in a mouse model where TAP deficiency had little or no effect in the tumor incidence [148], it was an obvious reminder of the correlation between MHC deficiency and cancer [149][150][151]. Furthermore, careful investigation of the protective mechanism demonstrated against viruses in MHC I deficiency might help us in the identification of viral proteins that are processed independently of TAP proteins.…”

Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy

“…28,29,32,35,36 In a recent study, we showed that GM-CSFinduced interstitial DC differentiation from human CD34 ϩ hematopoietic progenitor cells (HPCs) requires STAT5 activity. 32 However, inhibition of STAT5 promotes the development of CD34-derived DC subsets can be classified into 3 main categories: migratory DCs, lymphoidresident DCs, and plasmacytoid DCs.…”

“…75 However, human subjects with IRF8 mutations resulting in strongly reduced IRF8 activity show general loss of DCs in peripheral blood, 87 implicating a broader effect of IRF8 on human DC development. In addition to regulating subset distribution, STAT5 promotes expression of MHC class II transactivator protein (CIITA), 35 which is essential for transcriptional activity of the MHC class II promoter. Because STAT5 also stimulates DNA binding and transcriptional activity of NF-B, 88 GM-CSF-induced STAT5 activation may increase the intrinsic immunogenicity of DCs generated in the presence of GM-CSF.…”

Autoimmune response induced by dendritic cells exerts anti-tumor effect in murine model of leukemia

“…Dendritic cells-based immunotherapy has been used in patients with melanoma, lymphoma, renal cell carcinoma, colon, breast, ovarian, and prostate cancer, with evidence of enhanced T cells immunity and, in some cases, with clinical benefits [25][26][27][28][29][30][31]. In some studies, when vaccination of dendritic cells loaded with tumor antigens shared with normal host cells results in severe autoimmune disease with the suppression of tumor [32].…”