Lineage tree analysis of high throughput immunoglobulin sequencing clarifies B cell maturation pathways

Transitional (TR) B cells are immature B cells that have migrated from the bone marrow to peripheral lymphoid organs, but can still undergo selection against autoreactivity. TR cells that survive selection eventually develop into mature naïve B cells (CD27-IgD+, NA). Upon exposure to antigen, NA cells may become IgM memory (CD27+IgD+, MM) or "classical", classswitched memory (CD27+IgD-, SM) B cells. Although MM immunoglobulin (Ig) genes do not undergo class switching, they do undergo somatic hypermutation, albeit with lower frequency than SM. It has been postulated that MM B cells originate from T-independent immune responses, while SM cells originate from T-dependent responses. Alternatively, MM cells may be early emigrants from T-dependent germinal centers. Double negative B cells (CD27-IgD-, DN) have been said to be exhausted memory cells, but their precise origin is unclear. Therefore, a definitive elucidation of lineage relationships between these different B cell subsets is needed.