Figure 2.

Recent advances in human circulatory memory B cell (MBC) subphenotyping.

The diagram indicates the broad MBC populations, as recently defined in the peripheral blood of healthy donors [27]. Circulating MBCs can be segregated into six isotype-agnostic populations with different isotype distributions (displayed at right) based on the expression of CD45RB, CD27, CD73, CD95, CD11c, and CD19. Beginning with a naïve-proximal CD45RB⁺CD27^–CD73^–CD95^– ‘early’ memory phenotype, three phenotypically similar subpopulations (middle) iteratively gain expression of CD27, CD73, and CD95. It is unclear whether this represents a maturation continuum or independent cell lineages. Two transcriptionally distinct CD45RB^– subsets are also detected, including a naïve-distal (seemingly ‘advanced’) CD19^hiCD11c⁺ group reminiscent of ‘atypical’, CD21^lo, and other nonclassical B cells that have been elsewhere described [19,20,52,58,68] (top), and an IgG-dominant cluster that also demonstrates little to no expression of CD27, CD73, or CD95 (bottom). Subsets are positioned left-to-right in terms of signaling capacity following B cell receptor (BCR) ligation/CD40L stimulation but, coincidentally, also in approximate reference to their phenotypic similarity (based on cell surface marker expression) with naïve cells [27]. CD11a positivity and CD200 negativity may be used to further identify isotype-switched CD27^– MBC subsets [28]. Soluble (s)CD95L may promote plasmablast differentiation via CD95 ligation [51]; CD11c⁺ MBCs have been identified as developing in a germinal center (GC)-independent manner, while possessing the ability to seed secondary GCs and differentiate into antibody-secreting cells [19,20,68]. Created with BioRender.com.