M cell pockets of human Peyer's patches are specialized extensions of germinal centers

M cells in follicle-associated epithelium of Peyer's patches (PP) mediate antigen entrance into the underlying lymphoid tissue. To investigate the functional potential of B cells in this unique microcompartment, the expression of co-stimulatory molecules necessary for B-T cell interaction was examined in histologically normal human PP by three-color immunohistochemistry. In the M cell areas, CD80 / CD86 expression was much more frequent on memory (sIgD–CD20+) B cells than on naive (sIgD+CD20+) B cells. M cell areas identified by such co-expression of CD20 and CD80 / CD86 were always spatially related to germinal centers (GC). Contrary to the GC B cell phenotype (sIgD–CD20+CD80 / 86hiCD10+Bcl-2–), however, M cell-associated B cells with a high level of CD80 / CD86 were CD20loCD10–Bcl-2+, and adjacent memory T cells (CD3+CD45R0+) often expressed CD40L (CD154). Autologous peripheral blood B-T cell cocultures with purified protein derivative as antigen showed that the sIgD–CD80 / CD86hiCD20lo phenotype could indeed be generated during cognate B-T interactions, concurrent with CD40L up-regulation on memory T cells. Thus, this M cell-associated phenotype might result from B-T cell interactions in the course of antigen presentation by memory B cells, with subsequent CD40 engagement by CD40L-expressing cognate memory T cells. We propose that this M cell-associated event contributes to memory B cell survival and diversification of intestinal immunity, representing a specialized limb of GC function.