Abstract
By shaping T cell immunity, tolerogenic dendritic cells (tDCs) play critical roles in the induction of immune tolerance after transplantation. However, the role of long noncoding RNAs (lncRNAs) in the function and immune tolerance of dendritic cells (DCs) is largely unknown. Here, we found that the lncRNA MALAT1 is upregulated in the infiltrating cells of tolerized mice with cardiac allografts and activated DCs. Functionally, MALAT1 overexpression favored a switch in DCs toward a tolerant phenotype. Mechanistically, ectopic MALAT1 promoted dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) expression by functioning as an miR155 sponge, which is essential for the tolerogenic maintenance of DCs and the DC-SIGN-positive subset with more potent tolerogenic ability. The adoptive transfer of MALAT1-overexpressing DCs promoted cardiac allograft survival and protected from the development of experimental autoimmune myocarditis, accompanied with increasing antigen-specific regulatory T cells. Therefore, overexpressed MALAT1 induces tDCs and immune tolerance in heart transplantation and autoimmune disease by the miRNA-155/DC-SIGH/IL10 axis. This study highlights that the lncRNA MALAT1 is a novel tolerance regulator in immunity that has important implications in settings in which tDCs are preferred.
Highlights
Dendritic cells (DCs), as the most potent APCs, control the fate of the immune response and play critical roles in transplant immunity, the autoimmune response, cancer immunity, and infective immunity [1, 2]
We proposed that ectopic MALAT1 favors tolerogenic dendritic cell (tDC) possibly via dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) leading to enhanced IL10
We further evaluated whether the transfer of plasmids to overexpress MALAT1 (pMALAT1)-DCs was able to promote the secretion of cytokines and induce T cell hyporesponsiveness and found that the expression of inflammatory cytokines IL12 and IL6 in serum was significantly decreased, and the anti-inflammatory cytokine IL10 was increased in mice injected with pMALAT1-DCs (Figure 7F) but not in those transfused with LPS-DCs or phosphate-buffered saline (PBS)
Summary
Dendritic cells (DCs), as the most potent APCs, control the fate of the immune response and play critical roles in transplant immunity, the autoimmune response, cancer immunity, and infective immunity [1, 2]. Dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) is an innate immune receptor mainly expressed by DCs and macrophages. This receptor is involved in many aspects of DCs, including pathogen recognition and antigen presenting, and is considered a functional hallmark of DCs. DC-SIGN mediates the functions of DCs and macrophages in presenting and shaping T cell immunity [9,10,11,12,13]. We first identified the lncRNA MALAT1 in tolerized cardiac allografts and further elucidated the contribution of MALAT1 to the tolerogenic function of DCs and immune tolerance induction in heart transplantation and autoimmune disease
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