The body's mucosal surfaces are defended by a coating of immunoglobulin A. In the gut, IgA is secreted by antibody-forming cells (AFCs) that are positioned in a crucial immune-effector site — the villus lamina propria (LP). These IgA+ AFCs were thought to originate in germinal centres within descrete inductive immune sites known as Peyer's patches (PP). But a recent report in Nature from Tasuku Honjo's group shows that this is not the whole story.

An initial clue that the origins of IgA+ AFCs might be different came from studies of mice deficient in activation-induced cytidine deaminase ( AID ). B cells from AID−/− mice cannot switch their immunoglobulin class, and there is a striking accumulation of IgM+ B cells and AFCs in the gut LP. This led the authors to propose that the LP IgM+ B cells might be the precursors of both IgM+ LP AFCs in AID−/− mice and IgA+ AFCs in wild-type mice.

If LP IgA+ AFCs are generated in situ, then actively switching B cells should be present in the LP. But how can this transient event be detected? The authors used three molecular indicators: AID, which is expressed only in B cells undergoing class switching; germ-line transcripts of the α-chain gene, which are produced just prior to switching; and circular transcripts, which are short-lived by-products of class-switch recombination. These indicators show that both LP and PP IgA+ B cells have recently class-switched.

In vitro and in vivo experiments showed that LP IgM+ B cells have a greater tendancy than PP IgM+ B cells to differentiate into IgA+ AFCs. But what is it about the micorenvironment of the LP that supports switching from IgM to IgA, an event previously thought to be restricted to germinal centres? The authors show that stromal cells isolated from the LP enhance the switching of splenic B cells to IgA, and suggest that factors secreted by the stromal cells, particularly transforming growth factor-β, might promote differentiation to IgA+ AFCs.

This study indicates that, in addition to being a crucial effector site, the gut LP is an important inductive site of the gut mucosal immune system.