Model of human memory B-cell generation from GC-dependent and -independent pathways. Six purified memory B-cell subsets showed differential levels of proliferation and BCR maturation. Ig class-switching profiles and immunophenotyping of blood of CD40L-deficient patients supported delineation of these 6 subsets from T cell-dependent and -independent maturation pathways. CD27⁻IgA⁺ and natural effector B cells can be derived independently from T-cell help, probably locally in the gastrointestinal tract and from systemic responses in splenic marginal zone, respectively. The molecular profiles of CD27⁻IgG⁺ and CD27⁺IgM⁺ memory B cells resembled those of primary GC cells, whereas CD27⁺IgG⁺ and CD27⁺IgA⁺ memory B cells has increased proliferation and SHM levels suggestive of further maturation in consecutive GC response.