Distinct mucosal or systemic microbiota exposures shape the functional B cell repertoire

Microbiota colonization causes profound B cell stimulation and immunoglobulin induction, yet mammals colonized with many taxa have highly complex individualized immunoglobulin repertoires. To deconstruct how the microbiota shapes the B cell pool and its functional responsiveness we have used a simplified model of defined transient microbial exposures by different taxa in germ-free mice. B cell immunoglobulin repertoire development was followed by deep sequencing and in single cells. Intestinal mucosal exposure generated oligoclonal responses which differed from germ-free controls or from the diverse repertoire generated after intravenous systemic exposure. The IgA repertoire, predominantly to cell-surface antigens, did not expand following dose escalation, whereas increased systemic exposure broadened the IgG repertoire to both microbial cytoplasmic and cell-surface antigens. These microbial exposures induced characteristic immunoglobulin heavy chain B cell repertoires mainly at memory and plasma cell stages. Whereas sequential systemic exposure to different taxa diversified the IgG repertoire and facilitated alternate specific responses, sequential mucosal exposure produced limited overlapping repertoires and attrition of initial IgA binding specificities. This shows a contrast between a flexible response to systemic exposure with the need to avoid fatal sepsis, and a restricted response to mucosal exposure reflecting the generic nature of mucosal microbial mutualism.