CD137 Promotes Proliferation and Survival of Human B Cells

Abstract

CD137 (4-1BB)-mediated costimulation plays an important role in directing the fate of Ag-stimulated T cells and NK cells, yet the role of CD137 in mediating B cell function is unknown. We found that CD137 is expressed in vitro on anti-Ig–stimulated peripheral blood B cells and in vivo on tonsillar B cells with an activated phenotype. In vitro CD137 expression is enhanced by CD40 stimulation and IFN-γ and is inhibited by IL-4, -10, and -21. The expression of CD137 on activated human B cells is functionally relevant because engagement with its ligand at the time of activation stimulates B cell proliferation, enhances B cell survival, and induces secretion of TNF-α and -β. Our study suggests that CD137 costimulation may play a role in defining the fate of Ag-stimulated human B cells.

4-1BB signaling beyond T cells

“…4-1BB expression on human B cells was also unregulated by anti-CD40/anti-Ig, and in combination with IFN-c, but not when IL-2, -6 and -15, and TNF-a were used. 28 Interestingly, addition of either IL-4, IL-10 or IL-21 to B cells in the presence of anti-CD40/ anti-Ig caused downregulation of 4-1BB expression. 28 When P815 cells, transfected to express 4-1BBL, were co-incubated with human B cells, they increased their survival, enhanced their proliferation and unregulated TNF-a and -b, suggesting that 4-1BB expression by B cells is functional.…”

“…28 Interestingly, addition of either IL-4, IL-10 or IL-21 to B cells in the presence of anti-CD40/ anti-Ig caused downregulation of 4-1BB expression. 28 When P815 cells, transfected to express 4-1BBL, were co-incubated with human B cells, they increased their survival, enhanced their proliferation and unregulated TNF-a and -b, suggesting that 4-1BB expression by B cells is functional. The identification of 4-1BB 1 B cells in the germinal centers of tonsils indicates a possible role in humoral immunity.…”

“…27 4-1BB transcripts were observed more than a decade ago in human B cells stimulated by phorbol myristate acetate and anti-Ig Abs, 22 but possible functional consequence were not explored. Recently, Zhang et al 28 demonstrated that 4-1BB was expressed by human B cells when total peripheral blood monocytic cells were activated with pokeweed mitogen but not when purified B cells were used. 4-1BB expression on human B cells was also unregulated by anti-CD40/anti-Ig, and in combination with IFN-c, but not when IL-2, -6 and -15, and TNF-a were used.…”

Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

“…CD137 expression can also be induced on dendritic cells (15), tumor endothelial cells (16), B cells (17), and myeloid leukocytes (18) upon activation.…”

Functional expression of CD137 (4-1BB) on T helper follicular cells

“…20 Interestingly, staining in interfollicular areas was very scattered, whereas expression in the marginal zone around and inside the germinal center of the follicles was more prominent (Fig. 1D).…”