A germinal center-independent pathway generates unswitched memory B cells early in the primary response

Memory B cells can be produced from the classical germinal center (GC) pathway or a less understood GC-independent route. We used antigen-based cell enrichment to assess the relative contributions of these pathways to the polyclonal memory B cell pool. We identified a CD38 ⁺ GL7 ⁺ B cell precursor population that differentiated directly into IgM ⁺ or isotype-switched (sw) Ig ⁺ memory B cells in a GC-independent fashion in response to strong CD40 stimulation. Alternatively, CD38 ⁺ GL7 ⁺ B cell precursors had the potential to become Bcl-6 ⁺ GC cells that then generated primarily swIg ⁺ memory B cells. These results demonstrate that early IgM ⁺ and swIg ⁺ memory B cells are products of a GC-independent pathway, whereas later switched Ig ⁺ memory B cells are products of GC cells.