Inhibitory C-type lectin receptors in myeloid cells

Abstract

C-type lectin receptors encoded by the natural killer gene complex play critical roles in enabling NK cell discrimination between self and non-self. In recent years, additional genes at this locus have been identified with patterns of expression that extend to cells of the myeloid lineage where many of the encoded inhibitory receptors have equally important functions as regulators of immune homeostasis. In the present review we highlight the roles of some of these receptors including recent insights gained with regard to the identification of exogenous and endogenous ligands, mechanisms of cellular inhibition and activation, regulated expression within different cellular and immune contexts, as well as functions that include the regulation of bone homeostasis and involvement in autoimmunity.

Fig. 1

C-type lectin receptors encoded by the natural killer gene complex (NKC). The murine NKC comprises genes located on chromosome 6F3 and spans a region of approximately 2.5 Mb. In humans, its equivalent is located on chromosome 12p13.1. The dectin-1 cluster (black dashed square) comprises genes encoding group V CLRs including MICL (G), CLEC-2, CLEC-9A, MAH (H), CLEC-1, dectin-1 (B) and LOX-1. The dectin-2 cluster (black dotted square) comprises genes centromeric to the NKC which encode group II CLRs including BDCA-2, DCAR (A), DCIR (D), dectin-2, CLECSF8 and Mincle. The murine Ly49 family (black solid square) includes both activating receptors such as Ly49H (C) and inhibitory receptors such as Ly49Q (I). Genes encoding MAFA/KLRG1 (humans) and its murine orthologue (klrg1) are highlighted in solid grey squares. Names in italics represent genes present in humans but absent from the mouse NKC. Upper panels show activating receptors and bottom panels show inhibitory receptors, both in order of chromosomal localisation from left (centromeric) to right (telomeric). ITAM: ; ITIM: ●; ITAM-like: ○. Activating receptor substrates such as Src and Syk kinases and inhibitory receptor substrates such as protein tyrosine phosphatases SHP-1,-2 and SHIP are also shown. (E) Rat MAFA inhibits the secretory response induced by IgE-mediated FcɛRI aggregation, (G) human MICL ligation suppresses TLR-induced responses within specific immune and cellular contexts.

Fig. 2

Isoforms of inhibitory C-type lectin receptors. (A) Three alternatively spliced hMICL isoforms (α, β, γ). (B) Four different forms of alternatively spliced DCIR mRNA (v1–v4). (C) Four splice variants of the ly49q1 gene in mouse strains JF1, MSM and SV129 (Cyt, ΔCRD1, ΔCRD2, ΔCRD3). Arrows indicate translation stop codons.