CD137 Ligand Activities on B Cells

B cells, another group of APC, can also express CD137 ligand. Human and murine transformed B cells express CD137 ligand protein constitutively while activation may be required for primary B cells (Table 3.2).

Unlike in the case of monocytes and potentially dendritic cells, signals through CD137 ligand do not initiate activation of B cells. Rather, they enhance proliferation and immunoglobulin synthesis of preactivated B cells (Pauly et al., 2002; Pollok et al., 1994). In contrast to these in vitro data, constitutive expression of CD137 ligand on APC in transgenic mice causes a gradual elimination of peripheral B cells (Zhu et al., 2001). The CD137 ligand-transgenic mice have normal B cell numbers and functions up to the age of three months, and develop B cell deficiencies only later in life. This could indicate that initially the signals through CD137 ligand are activating for B cells, while prolonged CD137 ligand signals may be deleterious for B cell numbers and functions, possibly due to overstimulation. An alternative explanation would be that activated T cells or other CD137-expressing cells receive too much CD137 stimulation by being exposed to the CD137 ligand-expressing transgenic B cells, and in turn lead to an elimination of the B cells. Indeed, it has been shown that crosslinking of CD137 on monocytes causes them to induce apoptosis in B cells (Kienzle and von Kempis, 2000).

Costimulation of primary antibody response

Costimulation of secondary antibody response s^CD40 ligand c=c CD40 ra»"vCD137 >-c:> CD137 ligand

Figure 3.2. Depiction of the suggested roles of the CD40 and CD137 receptor/ligand systems in B cell maturation and the costimulation of humoral immune responses. At the first antigen encounter the CD40 receptor/ligand system costimulates B cell proliferation and immunoglobulin class switch. At the second antigen encounter during affinity maturation the CD137 receptor/ligand system costimulate B cell proliferation and immunoglobulin synthesis. FDC: follicular dendritic cell.

These functional data on CD137 ligand-mediated B cell activation are supported by histological findings. CD137 is expressed by follicular dendritic cells in germinal centers (Lindstedt et al., 2003; Pauly et al., 2002). B cells accumulate after first antigen encounter in these anatomical structures and undergo the process of affinity maturation. Follicular dendritic cells present the antigens in form of iccosomes to the B cells and play an essential role in the clonal selection of B cells with high affinity B cell receptors. Its expression on follicular dendritic cells allows CD137 to provide costimulatory and survival signals to those B cells, which have rearranged their immunoglobulin genes resulting in a high affinity binding to the antigen (Pauly et al., 2002).

The activities of CD137 and its ligand in B cell activation and development are reminiscent of those of the CD40 receptor/ligand pair, also members of the TNF receptor and ligand families. The CD40 receptor/ligand system mediates T cell help to B cells, which have encountered their specific antigen for the first time. It can be hypothesized that after somatic hypermutation of the complementary determining region, the second antigen encounter takes place on the surface of follicular dendritic cells, and here costimulation is mediated—at least in part—by the CD137 receptor/ligand system (Figure 3.2).

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