Abstract
Humoral immunity depends on intrinsic B cell developmental programs guided by systemic signals that convey physiologic needs. Aberrant cues or their improper interpretation can lead to immune insufficiency or a failure of tolerance and autoimmunity. The means by which such systemic signals are conveyed remain poorly understood. Hence, further insight is essential to understanding and treating autoimmune diseases and to the development of improved vaccines. ST6Gal-1 is a sialyltransferase that constructs the α2,6-sialyl linkage on cell surface and extracellular glycans. The requirement for functional ST6Gal-1 in the development of humoral immunity is well documented. Canonically, ST6Gal-1 resides within the intracellular ER-Golgi secretory apparatus and participates in cell-autonomous glycosylation. However, a significant pool of extracellular ST6Gal-1 exists in circulation. Here, we segregate the contributions of B cell intrinsic and extrinsic ST6Gal-1 to B cell development. We observed that B cell-intrinsic ST6Gal-1 is required for marginal zone B cell development, while B cell non-autonomous ST6Gal-1 modulates B cell development and survival at the early transitional stages of the marrow and spleen. Exposure to extracellular ST6Gal-1 ex vivo enhanced the formation of IgM-high B cells from immature precursors, and increased CD23 and IgM expression. Extrinsic sialylation by extracellular ST6Gal-1 augmented BAFF-mediated activation of the non-canonical NF-kB, p38 MAPK, and PI3K/AKT pathways, and accelerated tyrosine phosphorylation after B cell receptor stimulation. in vivo, systemic ST6Gal-1 did not influence homing of B cells to the spleen but was critical for their long-term survival and systemic IgG levels. Circulatory ST6Gal-1 levels respond to inflammation, infection, and malignancy in mammals, including humans. In turn, we have shown previously that systemic ST6Gal-1 regulates inflammatory cell production by modifying bone marrow myeloid progenitors. Our data here point to an additional role of systemic ST6Gal-1 in guiding B cell development, which supports the concept that circulating ST6Gal-1 is a conveyor of systemic cues to guide the development of multiple branches of immune cells.
Highlights
The humoral immune system is central to the successful management of infectious insults, through resolving established infections and generating long-term protection against future exposures
Our results show that cell non-autonomous ST6Gal-1 influences sialylation of marrow immature and IgM-high B cells and population size of splenic IgD-/CD21- cells
The inability to generate α2,6-sialyl glycans due to deficiency of the sialyltransferase ST6Gal-1 results in a plethora of humoral defects, including an attenuated response to antigenic challenges, FIGURE 5 | Systemic ST6Gal-1 influences long-term survival, but not homing of splenic B cells. (A) CFSE-labeled splenocytes from day 6 wild-type mice were intravenously injected into μMT and μMT/ST6KO mice. 24 h later, spleens were analyzed
Summary
The humoral immune system is central to the successful management of infectious insults, through resolving established infections and generating long-term protection against future exposures. Humoral insufficiency puts the host at risk, dysregulation of normal B cell function and development underlies autoimmune conditions such as lupus and rheumatoid arthritis. Sialylation in B Cell Development [1,2,3]. Immature B cells that successfully display the B cell receptor enter several transitional stages as they embark upon migration to the spleen [4]. During these stages, auto-reactive clones are selectively depleted by exposure to self-antigens—a critical regulatory step in prevention of autoimmunity [5]. The mechanisms controlling transitional B cell survival and development are significant to both the treatment of autoimmunity and development of improved immunization strategies
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