Heterogeneity in the differentiation and function of memory B cells

Abstract

Vaccines that induce neutralizing antibodies have led to the eradication of small pox and have severely reduced the prevalence of many other infections. However, even the most successful vaccines do not induce protective antibodies in all individuals, and can fail to induce lifelong immunity. A key to remedying these shortcomings may lie in a better understanding of long-lived memory B cells. Recent studies have revealed novel insights into the differentiation and function of these cells, and have shown that the memory B cell pool is much more heterogeneous than previously appreciated.

Figure 1. T dependent B cell differentiation in response to antigen

After BCR stimulation by antigen, rare naive B cells located within the follicle migrate to the border of the follicle and T cell area. Here, the activated B cells receive signals (CD40 via CD40L and various cytokines) from cognate CD4⁺ T cells, proliferate and adopt one of 3 fates: 1) Differentiate into memory B cells and migrate into the follicle; 2) Upregulate Blimp-1, migrate out of the follicle and become short-lived plasma cells; or 3). Upregulate Bcl-6, migrate deep into the follicle and establish germinal centers (GC). In the GC, B cells proliferate robustly and undergo CD4⁺ T cell-dependent affinity-maturation. Failure to receive signals from CD4⁺ T cells results in death while cells that receive signals can exit the GC as long-lived plasma cells or memory B cells. Most GC-derived memory B cells express isotype switched Ig (swIg) while most GC-independent memory B cells express IgM.

Figure 2. Early versus late memory B cells

The left box depicts a situation early after initial antigen exposure when both IgM⁺ and swIg⁺ memory B cells are present along with high titers of antigen-specific serum antibody. Upon secondary challenge, the serum antibody binds up much of the antigen and only the high-affinity swIg⁺ memory B cells respond. They form a large burst of swIg⁺ short-lived plasma cells, which boost the levels of serum antibody. They also form more swIg⁺ memory B cells, but they do not form GC B cells. The right box depicts a situation long after antigen exposure where antigen-specific serum antibody and swIg⁺ memory B cells have declined to very low or undetectable levels. The long-lived IgM⁺ memory B cells can now respond to the secondary challenge and form IgM⁺ and swIg⁺ plasma cells, GC B cells, and memory B cells.

Figure 3. High affinity IgE memory resides within affinity-matured IgG1⁺ memory B cells

Following antigen exposure and interaction with IL-4-producing CD4 helper T cells at the follicular border, B cells proliferate, isotype switch to IgG1 or IgE, and follow one of 2 fates: 1). Upregulate Blimp-1, migrate out of the follicle and become short-lived plasma cells; or 2). Upregulate Bcl-6, and migrate into the GC. IgE⁺ GC B cells appear to be rapidly shunted into the short-lived plasma cell pathway before affinity maturation can occur. In contrast, IgG1⁺ GC B cells undergo CD4⁺ T cell-dependent affinity-maturation and some exit the GC as long-lived plasma cells or memory B cells. Upon a second encounter with antigen, the GC-derived high-affinity IgG1⁺ memory cells form a rapid short-lived plasma cell response, where some of the cells undergo isotype switching from IgG1 to IgE.