CD163/WC1 functions as a pattern recognition receptor and co-receptor for the γδ TCR (113.18)

Abstract

Abstract CD163/WC1 proteins, specifically expressed by γδ T cells, are members of the scavenger receptor cysteine-rich (SRCR) domain family. Phosphorylation of a tyrosine in the WC1 cytoplasmic domain upon co-ligation of WC1 and TCR is required for the WC1 co-receptor activity. Two out of fourteen WC1 proteins contribute to the γδ T cell response to the spirochete Leptospira. Other closely related SRCR family members (e.g. DMBT1, CD6 and CD163A) bind to bacteria, suggesting that WC1 acts a signaling co-receptor in γδ T cell activation via Leptospira ligation. Jurkat cells expressing the chimeric protein CD4/WC1cyt, CD4/WC1cyt mutated on a dileucine endocytic motif, and CD4/WC1cyt mutated on two serines upstream of the dileucine motif were treated with PMA, resulting in endocytosis of wild type protein. The leucine mutants reduced PMA-induced endocytosis and enhanced IL-2 production stimulated by co-crosslinking of CD3 and CD4/WC1cyt, suggesting that sustained membrane co-ligation with CD3 increases WC1 signaling. The serine mutation had no effect on endocytosis, but did decrease IL-2 production, suggesting that serine phosphorylation of the cytoplasmic domain of WC1 is involved in T cell signaling. The N-terminal SRCR domain of the WC1 protein previously implicated in the Leptospira response binds strongly and specifically to Leptospira, supporting a model in which WC1 acts both as a pathogen recognition receptor (PRR) and a membrane proximal signaling co-receptor to the γδ TCR.