Activated human B cells: stimulatory or tolerogenic antigen-presenting cells?

To the editor:

In recent years the antibody-independent functions of B cells have gained increasing attention. B cells can become potent antigen-presenting cells (APCs) after activation. Contrary to activated B cells, resting B cells can act as immunoregulatory cells. Two interesting recent papers in Blood now show that activated human B lymphocytes can also obtain regulatory functions. The fact that activated B cells can inhibit T-cell responses is somewhat surprising, as we and others have shown that B cells stimulated via CD40 induce CD4⁺ and CD8⁺ T-cell responses in vitro and in vivo.^1-3  How can these discrepancies be explained?

Tretter et al show that activation by Staphylococcus aureus Cowan I (SAC) or CpG-containing oligonucleotides induces B cells which down-regulate T-cell responses by inducing anergy and apoptosis of CD4⁺ T cells in an IL-2–dependent fashion.⁴  The suppressive effect was restricted to the activated large B-cell subpopulation expressing the high-affinity interleukin-2 (IL-2) receptor CD25. CD25 expression is not a marker for B cells with regulatory function, though, because many other stimuli, including CD40 activation and IL-4, also induce CD25 expression. Like the regulatory B-cell population described by Tretter et al, CD40-activated B cells express CD25 as well as high levels of costimulatory molecules (Figure 1). Despite these similar features, they do activate T cells even in the presence of 50 U/mL IL-2, a concentration at which Tretter et al observed an inhibition of T-cell proliferation.^1,3  Therefore, the functional consequences of CD25 expression on activated B cells appear to be dependent on the activation stimulus. Bacterial activation by stimuli such as CpG, SAC, and lipopolysaccharide⁵  seem to confer regulatory functions whereas activation via CD40 induces stimulatory functions in B cells exposed to IL-2.^1,5  In addition, because SAC preferentially activates; immunoglobulin variable heavy chain gene 3 (VH3)–expressing B cells, it could be that suppressive function is characteristic for this subpopulation of B cells.⁶ 

It has previously been shown that murine and human resting B cells can expand regulatory T cells in vitro.^7,8  Tu et al demonstrate that alloantigen-specific human regulatory T cells can be generated in vitro using autologous CD40-activated (CD40-B) cells.⁹  The CD40-B cells seem to be more heterogeneous than typical CD40-B cells, though (Figure 1). Based on the expression of major histocompatibility complex class II, 2 distinct populations represented by 2 separate peaks can be identified in Figure 1C of their article. Because Tu et al used cryopreserved CD40-B cells, the process of cryopreservation and thawing might have affected the function of the CD40-B cells.

In conclusion, these 2 studies exemplify the activation state–dependent plasticity of B-cell function. Several factors such as the type, duration, and strength of the activation stimulus, the B-cell subset, and microenvironmental setting seem to determine the final outcome. The role of different modes of B-cell activation in determining B-cell function therefore requires further clarification. One should thus be cautious before drawing general conclusions about the function of activated B cells from studies that use only a limited set of activation stimuli.