Signaling and ligand interaction of ILT7: receptor-mediated regulatory mechanisms for plasmacytoid dendritic cells

Abstract

Plasmacytoid dendritic cells (pDCs) are specialized dendritic cells (DCs) that produce large amounts of type I interferon (IFN) after Toll-like receptor (TLR) activation. Human pDCs preferentially express immunoglobulin-like transcript 7 (ILT7; LILRA4), which couples with a signaling adapter to activate a prominent immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling pathway. ILT7 protein directly binds to and can be activated by bone marrow stromal cell antigen 2 (BST2; CD317) protein, the expression of which is found on cells pre-exposed to IFN or on the surface of human cancer cells. The interaction between ILT7 and BST2 functions to assure an appropriate TLR response by pDCs during viral infection and likely participates in pDC-tumor crosstalk. Two opposing modes of receptor-mediated regulatory mechanisms work jointly to fine tune the innate immunity of pDCs.

Fig. 1. Signaling activation of ILT7 downregulates TLR-mediated IFN and cytokine responses by pDCs

Mature ILT7 protein with an extracellular portion containing four immunoglobulin-like domain associates via its transmembrane region with the ITAM adapter FcεRIγ. The ILT7/FcεRIγ complex activates a receptor-proximal signal transduction cascade involving several protein kinases and cell type–specific signaling adapters, which potently suppresses TLR7/9-mediated IFN and cytokine production by pDCs while minimally affecting pDC maturation.

Fig. 2. Effects of the interaction between BST2 and ILT7 on pDCs

(Top) By sensing viral infection, pDCs can rapidly and rigorously produce large amounts of type I IFN via TLR7 or TLR9 activation. IFN then may induce the neighboring cells to express BST2, which in turn engages with ILT7 on pDCs to downregulate the magnitude of IFN and cytokine responses in a negative-feedback manner. (Bottom left) In a tumor environment where BST2 is endogenously expressed, infiltrating pDCs may be functionally suppressed to elicit normal IFN response to TLR ligands as a result of the interaction between BST2 and ILT7. (Bottom right) When coexpressed, ILT7 sequesters BST2 by inducing BST2 internalization as a result of cis-recognition.

Fig. 3. Innate immunity of pDCs is under control by two classes of surface receptors

Receptors signal through a shared ITAM-mediated pathway that mostly negatively regulates TLR7/9-mediated IFN and cytokine responses, whereas receptors containing ITIMs may have opposing effects on pDCs. Shown are the pDC receptors expressed by human (top) and mouse (bottom) pDCs.