Mechanisms of prolongation of allograft survival by HLA-G/ILT4-modified dendritic cells.

Engagement of inhibitory receptors on dendritic cells (DCs) is a powerful way to modulate their functions to achieve hyporesponsiveness or tolerance induction. Transgenic mice expressing human ILT4 receptor exclusively on DCs and triggered by HLA-G1 developed long-term survival of allogeneic skin transplant. Here we identify the cellular and molecular mechanisms responsible for that induction of hyporesponsiveness to alloantigen in vivo. Engagement of ILT4 receptor by HLA-G1 resulted in down-regulation of expression of MHC class II and costimulatory molecules, and modulation of cytokine production on DCs. HLA-G-modified DCs from ILT4 transgenic mice promote long-term survival of allografts by mechanisms involving both the induction of regulatory T cells and T-cell anergy. A novel feature of our research was to establish a model for the study of the prospective mechanisms of regulation of alloimmune responses by inhibitory receptors in vivo and analysis of the potential of HLA-G and its inhibitory receptors in modulation of DCs and T-cell function.