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

Summary 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.