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Review
. 2022 Dec 31;210(3):217-229.
doi: 10.1093/cei/uxac103.

A close-up on the expanding landscape of CD21-/low B cells in humans

Inger Gjertsson  1 , Sarah McGrath  1 , Kristoffer Grimstad  1   2 , Charlotte A Jonsson  1 , Alessandro Camponeschi  1 , Katrin Thorarinsdottir  1 , Inga-Lill Mårtensson  1
Affiliations
Review

A close-up on the expanding landscape of CD21-/low B cells in humans

Inger Gjertsson et al. Clin Exp Immunol. .

Abstract

Memory B cells (MBCs) are an essential part of our immunological memory. They respond fast upon re-encountering pathogens and can differentiate into plasma cells that secrete protective antibodies. The focus of this review is on MBCs that lack, or express low levels of, CD21, hereafter referred to as CD21-/low. These cells are expanded in peripheral blood with age and during chronic inflammatory conditions such as viral infections, malaria, common variable immunodeficiency, and autoimmune diseases. CD21-/low MBCs have gained significant attention; they produce disease-specific antibodies/autoantibodies and associate with key disease manifestations in some conditions. These cells can be divided into subsets based on classical B-cell and other markers, e.g. CD11c, FcRL4, and Tbet which, over the years, have become hallmarks to identify these cells. This has resulted in different names including age-associated, autoimmune-associated, atypical, tissue-like, tissue-resident, tissue-restricted, exhausted, or simply CD21-/low B cells. It is however unclear whether the expanded 'CD21-/low' cells in one condition are equivalent to those in another, whether they express an identical gene signature and whether they have a similar function. Here, we will discuss these issues with the goal to understand whether the CD21-/low B cells are comparable in different conditions.

Keywords: CD21–/low; age-associated; atypical; autoimmune-associated; exhaustion; memory B cells.

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Figures

Graphical Abstract
Graphical Abstract
Figure 1:
Figure 1:
Gating strategies for human B cell subsets. (A) Peripheral blood lymphocytes were gated on CD19+CD20+ and CD19+CD20+CD21–/low B cells, as indicated. Based on CD27 and IgD expression, the cells can be divided into switched memory (Sw), unswitched memory (UnSw), double negative (DN) memory as well as naive and transitional B cells. (B) B cells show heterogeneous expression of CD11c and Tbet, ranging from negative to high levels, showing that high expression levels are largely found on CD21–/low B cells.
Figure 2:
Figure 2:
Cartoon depicting phenotypes of CD21–/low memory B cells (MBCs) in tonsils and peripheral blood (PB). In healthy individuals, CD21–/low MBCs in tonsils are FcRL4+, whereas in PB they are Tbethi. The expression of these two markers in PB CD21–/low MBCs in the indicated conditions is shown. Shown is also expression of additional markers according the key. In some conditions, CD21–/low MBCs express different isotypes. Rheumatoid arthritis (RA), hepatitis C virus (HCV), systemic lupus erythematosus (SLE), common variable immunodeficiency (CVID), human immunodeficiency virus (HIV). *In SLE, CD21–/low MBCs have been shown to be FcRL4+ in one study and FcRL4– in another. ? indicates unclear expression.
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