Multiple mechanisms of immune suppression by B lymphocytes

Abstract

Suppression of the immune system after the resolution of infection or inflammation is an important process that limits immune-mediated pathogenesis and autoimmunity. Several mechanisms of immune suppression have received a great deal of attention in the past three decades. These include mechanisms related to suppressive cytokines, interleukin (IL)-10 and transforming growth factor (TGF)-β, produced by regulatory cells, and mechanisms related to apoptosis mediated by death ligands, Fas ligand (FasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), expressed by killer or cytotoxic cells. Despite many lines of evidence supporting an important role for B lymphocytes as both regulatory and killer cells in many inflammatory settings, relatively little attention has been given to understanding the biology of these cells, their relative importance or their usefulness as therapeutic targets. This review is intended to give an overview of the major mechanisms of immunosuppression used by B lymphocytes during both normal and inflammatory contexts. The more recent discoveries of expression of granzyme B, programmed death 1 ligand 2 (PD-L2) and regulatory antibody production by B cells as well as the interactions of regulatory and killer B cells with regulatory T cells, natural killer T (NKT) cells and other cell populations are discussed. In addition, new evidence on the basis of independent characterizations of regulatory and killer CD5(+) B cells point toward the concept of a multipotent suppressor B cell with seemingly high therapeutic potential.

Figure 1

Normal immune responses depend on appropriate levels of immune suppression. This schematic depicts three potential outcomes of an infection and the resulting inflammatory responses on the basis of varying the level and dynamics of immune suppression. (A) In a normal immune response, the infectious agent stimulates an early inflammatory response that begins to control the infection before immune suppression begins. As the infection is cleared, inflammation decreases while immune suppression continues to increase, resulting in the resolution of inflammation and return to homeostasis. (B) An immune response with delayed or weakened immune suppression leads to increased inflammation and impaired resolution despite the absence of the eliciting infectious agent. If unresolved, this scenario would lead to severe acute inflammation and death. (C) Early and/or increased suppression may inappropriately lower inflammation and prevent clearance of the infectious agent. Depending on the nature of the infection and the balance between inflammation and suppression, this result could lead to morbidity caused by the infectious agent, a chronic state of inflammation and/or higher baseline suppression toward the next inflammatory stimulus. , Infection; , inflammation; , immune suppression.

Figure 2

B-cell subsets can mediate immune suppression through multiple effector mechanisms. The major pathways involved in immune suppression have been shown to be expressed by various subsets of B lymphocytes. T2-MZP and B10 cells have been independently described as important B-cell sources of IL-10, but IL-10 might also be produced by any B cell given the proper stimulus. In some cases, TGFβ has also been shown to be produced by B cells, but the phenotype of these cells is undetermined. Human but not mouse B cells have been shown to express granzyme B, the enzymatic component of cytotoxic granules. B cells expressing PD-L2 on the cell surface (L2pB1 cells) can send either stimulatory or regulatory signals through interactions of PD-L2 with the receptor PD-1 on target cells. Killer B lymphocytes are defined by expression of the death ligands FasL and/or TRAIL. The CD5⁺ B-cell subset has been independently reported to express IL-10, PD-L2, granzyme B (in humans) and FasL, suggesting that CD5⁺ B lymphocytes may function as multipotent suppressor B cells. CD4⁺ T cells are documented targets of immune suppression by B cells, but many of the mechanisms described also have effects on NKT cells, CD8⁺ T cells, APCs and other lymphoid and nonlymphoid cells.