Cutting Edge: FcR-Like 6 Is an MHC Class II Receptor

Receptors for the Fc portion of Ig have been extensively characterized and are known to regulate humoral responses , but members of the closely related FcR-like (FCRL) family have not been found to bind Ig, and to date, no ligand has been identified for any FCRL. Using a cell-based GFP reporter system and a recombinant Fc chimeric protein, we show that human FCRL6, a receptor selectively expressed by cytotoxic T and NK cells, directly binds HLA-DR, an MHC class II molecule. Given the similarity among constant regions of Ig and MHC molecules, these findings suggest that representatives of the FcR and FCRL multigene families may have independently evolved to engage two ancestral elements fundamental to adaptive immunity. This discovery may offer new insight into the interaction between cytotoxic lymphocytes and APCs and may have important implications for better understanding HLA disease susceptibility and pathogen-esis. T he characterization in recent years of multiple receptor -gene families with activating or inhibitory potential has disclosed that the immune system is integrated with a remarkable number of regulatory mechanisms to balance effector responses. The classical FcRs for IgG and IgE are located on human chromosome 1q21-23 and play fundamental roles in both positive and negative immune regulation (1–3). The discovery of an extended family of FcR-like (FCRL) genes (FCRL1–6) positioned in the same human chromosomal region has uncovered unexpected diversity at this locus (4–6). In addition to their genomic linkage and similar genetic organization , FCRL1–6 share many features with the FCRs, including related extracellular Ig-like domains and cytoplasmic tyrosine-based signaling capability of their encoded type I transmem-brane protein products (6). Of these, human FCRL6 is distinctly expressed by cytotoxic T and NK cells, is upregulated on expanded populations of terminally differentiated CD8 + T cells in patients with HIV and B cell chronic lymphocytic leukemia, and possesses a cytoplasmic ITIM that is capable of being phosphorylated and recruiting the Src homology 2-domain containing phosphatase 2 (7, 8). Despite the many similarities between the FcR and FCRL families, no FCRL has been shown to bind Ig, and thus ligands for these receptors remain unknown. In this study, we report that the MHC class II molecule HLA-DR is a ligand for human FCRL6. Using a cell-based reporter system, FCRL6 li-gand reactivity was found to be restricted to APCs, and the development of a panel of blocking Abs facilitated the identification of HLA-DR as the interacting …