CD21–/low B cells in human blood are memory cells

The complement receptor 2 (CR2, CD21) is part of a complex (CD21/CD19/CD81) acting as a co‐receptor to the B cell receptor (BCR). Simultaneous triggering of the BCR and CD21 lowers the threshold for B cell activation. Although CD21 is important, B cells that express low amounts or lack surface CD21 (CD21^–/low) are increased in conditions with chronic inflammation, e.g. autoimmune diseases. However, little is known about the CD21^–/low B cell subset in peripheral blood from healthy donors. Here, we show that CD21^–/low cells represent approximately 5% of B cells in peripheral blood from adults but are barely detectable in cord blood, after excluding transitional B cells. The CD21^–/low subset can be divided into CD38^–24⁺ and CD38^–24^low cells, where most of the CD38^–24⁺ are CD27⁺immunoglobulin (Ig)M⁺IgD⁺ and the CD38^–24^low are switched CD27^–. Expression levels of additional markers, e.g. CD95 and CD62L, are similar to those on classical memory B cells. In contrast to naive cells, the majority of CD21^–/low cells lack expression of the ABCB1 transporter. Stimulation with a combination of BCR, Toll‐like receptor (TLR)?7/8 and interleukin (IL)?2 induces proliferation and differentiation of the CD21^–/low B cells comparable to CD21⁺CD27⁺ memory B cells. The response excluding BCR agonist is not on par with that of classical memory B cells, although clearly above that of naive B cells. This is ascribed to a weaker response by the CD38^–24^low subset, implying that some memory B cells require not only TLR but also BCR triggering. We conclude that the CD21^–/low cells in healthy donors are memory B cells.