TOSO, the Fcμ Receptor, Is Highly Expressed on Chronic Lymphocytic Leukemia B Cells, Internalizes upon IgM Binding, Shuttles to the Lysosome, and Is Downregulated in Response to TLR Activation

TOSO/FAIM3 recently has been identified as the long-sought-after FcR for IgM (Fc mu R). Fc mu R is expressed on human CD19(+) B cells, CD4(+)/CD8(+) T cells, and CD56(+)/CD3(-) NK cells and has been shown to be overexpressed in chronic lymphocytic leukemia (CLL) cells. CLL is a malignancy of mature IgM(+) B lymphocytes that display features of polyreactive, partially anergized B cells related to memory B cells. In this article, we report that Fc mu R is O-glycosylated in its extracellular domain and identify the major sites of O-glycosylation. By using immunofluorescence confocal microscopy, we found that Fc mu R localized to the cell membrane but also found that large pools of Fc mu R accumulate in the trans-Golgi network. Aggregation of Fc mu R on CLL cells by IgM prompted rapid internalization of both IgM and Fc mu R, reaching half-maximal internalization of cell-bound IgM within 1 min. Upon internalization, Fc mu R transported IgM through the endocytic pathway to the lysosome, where it was degraded. Using a series of Fc mu R deletion mutants, we identified a proline-rich domain essential for cell surface expression of Fc mu R and a second domain, containing a YXX Phi motif, that controls internalization. Although it has been reported that BCR activation increases Fc mu R expression, we found that activation of TLRs strongly downregulated Fc mu R at both the mRNA and protein levels. Through internalization of IgM bound immune complexes, Fc mu R may play a role in immune surveillance and contribute to B cell activation. In addition, Fc mu R deserves study as a potential pathway for the delivery of therapeutic Ab-drug conjugates into CLL cells. The Journal of Immunology, 2011, 187: 4040-4050.