CD137 Ligand Activities on T Cells

Expression of CD137 ligand protein could either not be detected on primary T cells, or only at low levels. But CD137 ligand is present on human and murine T cell lines (Table 3.2). It may be that CD137 ligand is expressed on primary T cells at such low levels that detection by commonly used detection methods such as flow cytometry is difficult. T cell lines may acquire stronger CD137 ligand expression during the transformation process.

The activities of CD137 ligand on T cells stand in contrast (1) to its activities on APC, and (2) to the activities of CD137 on T cells. The signal through CD137 ligand downregulates T cell activity. Coculture of anti-CD3-activated human PBMC with CD137-expressing transfected CHO or COS-7 cells completely inhibits proliferation and induces cell death by apoptosis. Anti-CD137 ligand antibodies and recombinant CD137 protein have the same effects. Recombinant CD137 protein works only when it is immobilized on the tissue culture plates, or crosslinked via secondary antibodies while it is inactive when added as a soluble protein, demonstrating also for T cells that these effects are mediated by crosslinking CD137 ligand (Ju et al., 2003; Schwarz et al., 1996).

The inhibitory effect of CD137 ligand on T cells is also evident in vivo. Splenocytes from CD137-deficient mice respond with an increased proliferation to stimulation with mitogens or anti-CD3. Addition of a CD137 ligand signal by cocultivating CD137-deficient splenocytes with CD137-expressing cells reduces their proliferation to the level of wild-type cells (Kwon et al., 2002). At present it is not clear whether CD137 exerts this inhibitory effects directly by crosslinking CD137 ligand on T cells, or indirectly via other CD137 ligand-expressing cells.

In contrast to signals through CD137 which are generally costimulatory for T cells, signals through CD137 ligand are inhibitory. CD95 and CD95 ligand, two other members of the TNF receptor and TNF families, respectively, exert similar opposite effects on T cells. Although the signal through CD95 induces apoptosis in CD8-positive T cells, the signal through CD95 ligand is costimulatory (Suzuki and Fink, 1998).

Not much is known about the underlying mechanism of the T cell inhibitory activities of CD137 ligand. Although CD137 ligand signaling induces expression of CD95 on CD4- and CD8-positive T cells and on B cells, induction of apoptosis does not seem to involve CD95 (Michel et al., 1999). For one, antagonistic CD95 antibodies do not block CD137 ligand-induced apoptosis, and secondly, CD137 ligand induces apoptosis in resting as well as activated lymphocytes, while CD95-induced apoptosis is restricted to activated lymphocytes. Also, apoptosis signals through CD137 ligand are less potent and have a slower kinetic than apoptosis

CD137-ex-

pressing cell

CD137-ex-

pressing cell

CD137-ex-

pressing cell

CD137 ligand ra>ACD137 Other costimulatory receptor/ligand pair

Figure 3.3. Role of the CD137 receptor/ligand system in (A) the initiation and maintenance, and(B) the downregulation of T cell responses. (A) At the beginning of an immune response T cells receive activating signals from dendritic cells (DC) through CD137 and other costimulatory molecules. The inhibitory signals through CD137 ligand are blocked by activating signals. (B) Once the cause of the immune response has been eliminated, the dendritic cell will no longer provide activating signals and inhibit CD137 ligand-mediated apoptosis in T cells. Among the CD137-expressing cells, which can crosslink CD137 ligand on T cells and initiate apoptosis are also activated T cells. Therefore, in this phase of an immune response the number and density of activated T cells correlates with the inhibitory signals through CD137 ligand.

CD137-ex-

pressing cell

CD137 ligand ra>ACD137 Other costimulatory receptor/ligand pair

Figure 3.3. Role of the CD137 receptor/ligand system in (A) the initiation and maintenance, and(B) the downregulation of T cell responses. (A) At the beginning of an immune response T cells receive activating signals from dendritic cells (DC) through CD137 and other costimulatory molecules. The inhibitory signals through CD137 ligand are blocked by activating signals. (B) Once the cause of the immune response has been eliminated, the dendritic cell will no longer provide activating signals and inhibit CD137 ligand-mediated apoptosis in T cells. Among the CD137-expressing cells, which can crosslink CD137 ligand on T cells and initiate apoptosis are also activated T cells. Therefore, in this phase of an immune response the number and density of activated T cells correlates with the inhibitory signals through CD137 ligand.

signals through CD95, taking days rather than hours until apoptosis is significantly noticeable (Schwarz etal., 1996; Michel etal., 1999).

What could be the physiological function of the inhibitory activities of CD137 ligand on T cells? No studies have been reported addressing this question. It may be that CD137 ligand provides a negative feedback signal to T cells. CD137 expression on T cells is strictly activation-dependent. With a mounting immune response and an accompanying increasing density of CD137-expressing T cells, the inhibitory signals through CD137 ligand would also increase. But as long as the antigen is present, activated APC will express CD137 ligand and other costimulatory molecules, which may block the inhibitory CD137 ligand signals (Figure 3.3A). However, when the antigen has been cleared, APC will no longer provide costimulation and the inhibitory activities of CD137 ligand may become predominant, thereby contributing to the downsizing of a no longer needed antigen-specific T cell response (Figure 3.3B).

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