Cosmc controls B cell homing

Abstract

The molecular mechanisms regulating lymphocyte homing into lymph nodes are only partly understood. Here, we report that B cell-specific deletion of the X-linked gene, Cosmc , and the consequent decrease of protein O-glycosylation, induces developmental blocks of mouse B cells. After transfer into wild-type recipient, Cosmc -null B cells fail to home to lymph nodes as well as non-lymphoid organs. Enzymatic desialylation of wild-type B cells blocks their migration into lymph nodes, indicating a requirement of sialylated O-glycans for proper trafficking. Mechanistically, Cosmc -deficient B cells have normal rolling and firm arrest on high endothelium venules (HEV), thereby attributing their inefficient trafficking to alterations in the subsequent transendothelial migration step. Finally, Cosmc -null B cells have defective chemokine signaling responses. Our results thus demonstrate that Cosmc and its effects on O-glycosylation are important for controlling B cell homing.

Cosmc deficiency causes spontaneous autoimmunity by breaking B cell tolerance

“…4E ). These results mirror our previously observed difference in basal serum IgG3 level, which was extremely low in BC- Cosmc KO mice ( 23 ). These data indicate that Cosmc plays an essential role in mediating isotype switching to IgG3.…”

“…To functionally characterize these B cell subsets, we used flow cytometry to measure their uptake of a model antigen trinitrophenol (TNP)–Ficoll, which is a T-independent antigen that is quickly trapped by MZB and marginal zone precursor (MZP) after intravenous injection ( 38 ). We observed comparable binding of TNP-Ficoll in both WT and BC- Cosmc KO MZB cells, functionally confirming that the increased B cell subset in BC- Cosmc KO mice is MZB cells ( 23 ). By contrast, Cosmc -deficient FO B cells demonstrated significantly higher ability to bind to TNP-Ficoll ( Fig.…”

“…We observed enlarged spleen in young (2 to 4 months) ( 23 ) but not in aged (11 to 20 months) male BC- Cosmc KO mice (fig. S1D, left).…”

“…2A and fig. S2A) ( 23 ), which may result from a generalized hyperactivation of B cells. Flow cytometry analysis indicated that Cosmc -deficient B cells display enhanced basal activation, as measured by the surface expression of activation markers, including CD86, CD80, and major histocompatibility complex class II (MHC II) ( Fig.…”

“…The generation of O-glycans, which are abundantly present on leukocytes ( 18 – 22 ), requires expression of both Cosmc ( C1GalT1C1 ), a molecular chaperone in the endoplasmic reticulum, and its only client, the Core 1 β3galactosyl-tranferase ( C1GalT1 ), also known as T-synthase. We recently demonstrated that deletion of Cosmc in murine B cells, which results in expression of the Tn antigen (GalNAcα1-Ser/Thr/Tyr), greatly reduces their migration to lymph nodes ( 23 ). We also observed that the B cell-specific Cosmc -knockout (BC- Cosmc KO) mice displayed splenomegaly and hypergammaglobulinemia, indicating the potential development of AID.…”