Ly49 and C-type lectin receptors on dendritic cells regulate T-cell differentiation as co-stimulatory molecules

Abstract

The C-type lectin receptors (CLRs) expressed on dendritic cells (DCs) participate in T-cell polarization by recognizing pathogen-associated molecular patterns and activating signaling pathways for cytokine production. In addition, some CLRs expressed on DCs function as co-stimulatory molecules via recognition of endogenous ligands on T cells and regulate proliferation and/or differentiation of T cells. We recently showed that killer cell lectin-like receptor Ly49s3 is expressed in rat thymic DCs and recognizes MHC class I molecules on T cells, for differentiation into naturally occurring regulatory T cells (nTregs). Upon binding to MHC class I molecules on T cells, Ly49s3 seems to stimulate signal transduction pathway(s) leading to up-regulation of the MHC class II genes and then functions as a co-stimulatory molecule. The signaling pathway(s) is supposed to involve Dap12, Syk/Zap70, Lat, Plc-gamma, PKC, PU.1 and C2ta proteins to attain MHC class II expression. Other than Ly49s3, Ly49Q and Ly49B have been shown to be expressed in myeloid cells including DCs and macrophages, raising the possibility that they may be involved in the regulation of T-cell differentiation through recognition of MHC class I molecules on T cells. In humans, immunoglobulin (Ig)-like receptors binding to MHC class I molecules take the place of Ly49 receptors. Among them, expression of the KIR2DL4 gene has been reported to be induced in antigen-presenting cells, although its biological significance is obscure, and immunoglobulin-like transcript 4 (ILT4) expressed in DCs has been shown to down-regulate expression of MHC class II molecules on the same cells, upon binding to MHC class I molecules. They may also be involved in regulation of T-cell differentiation. Some other CLRs are expressed on DCs and possibly function as co-stimulatory molecules. For example, dectin-1, dectin-2 and Dcal-1 have been shown to promote T-cell proliferation, Treg differentiation and IL-4 production of T cells, respectively, through binding to unidentified ligands on T cells. DC-Sign, which recognizes ICAM3 on T cells, is also suggested to be involved in T-cell differentiation. Further investigation of the functional roles of CLRs on DCs will provide insight into the regulatory mechanisms of T-cell differentiation, essential processes for regulating immune responses.