Mucosal or systemic microbiota exposures shape the B cell repertoire

Abstract

Microbiota colonization causes profound B cell stimulation and immunoglobulin induction, yet mammals colonized with many taxa have highly complex individualized immunoglobulin repertoires 1,2 . 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 3 . 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 cellsurface 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. TEXTMammalian immunoglobulins (Ig) are composed of heavy (H) and light (L) chains, each assembled from one of many V H/L , (D H ) and J H/L gene segments during B cell development. The resulting genetic and structural immunoglobulin repertoire diversity and antigen recognition possibilities are further increased by additional nucleotide insertion during recombination, later somatic mutation, or class switch recombination from IgM and/or IgD to IgG, IgE or IgA. Selection and clonal expansion of particular B cells with an appropriate immunoglobulin specificity endows the system to respond to a huge variety of antigens.Comparisons of colonized and germ-free animals show that B cell numbers and immunoglobulin levels (especially IgG and IgA) are considerably amplified by colonization with a microbiota, some of which penetrate mucous membranes to prime systemic secondary lymphoid structures even in healthy hosts. 4,5 B cell repertoires have so far been shown to be largely unique to each individual animal 1,2 , although whether this is caused by differences in microbiota composition or the sequence of colonization in each animal is unknown.Using localized time-limited exposures of defined doses of single benign microbial taxa in germ-free animals 3 , we have addressed how the B cell repertoire is shaped by microbiota exposure at mucous membranes or in systemic lymphoid tissues, and how interactions between different exposure sites or subsequent exposures to different taxa affects the outcome. Distinct B cell Ig repertoires to intestinal microbes de...

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