Lecture series Infection & Immunity: "DISTINCT MUCOSAL OR SYSTEMIC RESPONSES TO NON-PATHOGENIC INTESTINAL MICROBES BUILD THE BASELINE B CELL REPERTOIRE AND ITS FUNCTIONAL RESPONSIVENESS" - Prof Andrew Macpherson

Microbiota colonization causes profound B cell stimulation and immunoglobulin induction. To understand how the B cell repertoire develops we have used transient reversible microbial exposures in germ-free mice. Distinct oligoclonal responses to all isotypes after intestinal mucosal exposure differ from those after intravenous systemic exposure or germ-free controls. The selective IgA repertoire after intestinal dose escalation becomes progressively restricted and clonally related, whereas the systemic IgG repertoire can be broadened to a range of microbial cytoplasmic as well as cell-surface antigens. There are hierarchical repertoires during different stages of B cell development which are dominantly shaped by microbial exposure at memory and plasma cell stages. Single cell analysis showed that the repertoire specificity was determined by the immunoglobulin heavy chain. Whereas sequential systemic exposure to different taxa broadens the IgG repertoire and multiplies specific responses, sequential mucosal exposure produces limited overlapping repertoires and attrition of initial IgA binding specificities. This shows a contrast between a flexible response to systemic exposure consistent with the need to avoid fatal sepsis and a restricted response to mucosal exposure reflecting the generic nature of mucosal microbial mutualism.

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