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Originally published online as doi:10.1189/jlb.0904558 on December 23, 2004

Published online before print December 23, 2004
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(Journal of Leukocyte Biology. 2005;77:281-286.)
© 2005 by Society for Leukocyte Biology

Biological activities of reverse signal transduction through CD137 ligand

Herbert Schwarz1

Department of Physiology, National University of Singapore

1 Correspondence: Department of Physiology, National University of Singapore, 2 Medical Drive, MD 9, Singapore 117597. E-mail: phssh{at}nus.edu.sg


   ABSTRACT
TOP
 ABSTRACT
SCOPE OF THIS REVIEW
 CD137 REVERSE SIGNALING
 PERSPECTIVE
 SUMMARY
 REFERENCES
 
CD137 is a member of the tumor necrosis factor receptor family and a potent regulator of T cell activities. Agonists of CD137 have been used widely and successfully to treat cancer in animal models, and recently, it has become evident that CD137 agonists can also be used to treat autoimmune disease. An aspect of the CD137 receptor/ligand system, which has been comparatively little-explored, is its ability of reverse signaling. Just as is CD137, the CD137 ligand is also expressed as a cell membrane protein, and it too can transduce signals into the cells on which it is expressed. This bidirectional signaling capacity allows the CD137 receptor/ligand system to mediate extensive cross-talk between immune cells and between immune and nonimmune cells. This review summarizes the known activities of the CD137 ligand on the different leukocyte subsets and on cancer cells and discusses their influence on the course of immune responses.

Key Words: TNF superfamily family • reverse signaling • bidirectional signal transduction


   SCOPE OF THIS REVIEW
TOP
 ABSTRACT
 SCOPE OF THIS REVIEW
CD137 REVERSE SIGNALING
 PERSPECTIVE
 SUMMARY
 REFERENCES
 
The genes for murine and human CD137 (4-1BB, induced by lymphocyte activation) have been cloned more than 15 and 10 years ago, respectively, and increasingly, CD137 enjoys the attention of a larger group of scientists [1 , 2 ]. CD137 has been identified as a potent T cell costimulatory molecule and a promising target for immunotherapy of cancer and autoimmune disease. Several excellent reviews provide a comprehensive overview over the various activities of CD137 on T cells and their potential therapeutic applications [3 4 5 6 ].

An activity of the CD137/CD137 ligand biology, which has received less attention, is its ability of reverse signal transduction, i.e., signaling through the CD137 ligand. It is the aim of this review to summarize and put into perspective what is known about this side of the CD137/CD137 ligand biology.


   CD137 REVERSE SIGNALING
TOP
 ABSTRACT
 SCOPE OF THIS REVIEW
 CD137 REVERSE SIGNALING
PERSPECTIVE
 SUMMARY
 REFERENCES
 
Bidirectional signal transduction refers to signal transduction through the receptor as well as its respective ligand, and reverse signaling specifically refers to signaling through the ligand. The CD137/CD137 ligand system shares the ability of bidirectional signal transduction and reverse signaling with many other members of the tumor necrosis factor receptor (TNFR) and TNF families [7 , 8 ]. Reverse signaling in the TNF family is possible, as most of its members are expressed as membrane proteins with cytoplasmic domains [9 , 10 ]. The designation as ligands for these molecules is based on historical reasons, but in functional terms, they would be described more aptly as coreceptors.

In comparison with other members of the TNF and TNFR families, bidirectional signal transduction and reverse signaling have been studied relatively well for the CD137 receptor/ligand system (Table 1 ). In the following, the description of the effects of CD137 ligand signaling is organized according to the cell types involved.


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  		Table 1. Activities of CD137 Ligand Signaling by Cell Type

 
CD137 ligand activities on monocytes/macrophages
Constitutive CD137 ligand expression was detected on peripheral monocytes and monocyte/macrophage cell lines (Table 2 ).


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  		Table 2. CD137 Ligand Protein Expression by Tissue

 
Cross-linking of the CD137 ligand by recombinant CD137 protein induces adherence, morphological changes, expression of proinflammatory cytokines (TNF, IL-6, IL-8, IL-12), and activation markers (ICAM-1) and inhibits expression of anti-inflammatory cytokines (IL-10) and differentiation markers (Fc{gamma}RIII) in monocytes [11 12 13 ]. Further, it induces expression of M-CSF, an essential survival factor for monocytes and thereby significantly prolongs survival of monocytes in vitro [14 ]. It was therefore surprising to find that the CD137 ligand also enhances the rate of apoptosis in monocytes. However, signaling through the CD137 ligand also induces proliferation and endomitosis of monocytes, which overcompensate the loss of cells through apoptosis. The potency of the CD137 ligand in stimulating proliferation in monocytes is profoundly higher than that of other monocyte growth factors such as M-CSF or granulocyte M-CSF [15 , 16 ]. Concurrent induction of apoptosis together with activation and proliferation is well known in lymphocytes as activation-induced cell death [35 ]. Although as an activator, CD137 is less potent than classical monocyte activators such as LPS, it is in inducing proliferation that the CD137 ligand exceeds the potency of other monocyte growth factors [12 ].

Recombinant CD137 protein or anti-CD137 ligand antibodies need to cross-link the CD137 ligand to exert these effects on monocytes. This can be achieved by coating the proteins onto tissue-culture plates or cross-linking them via secondary antibodies. Soluble recombinant CD137 protein has no effect, illustrating that it exerts its activities by cross-linking the CD137 ligand on monocytes [11 ].

Recently, the activating effects of the CD137 ligand on monocytes could be confirmed in vivo. Transgenic mice overexpressing the CD137 ligand on antigen-presenting cells (APC) develop a threefold, increased number of membrane-activated complex 1-positive cells [17 ]. CD137 ligand-deficient mice, conversely, have an increased number of myeloid progenitor cells in the peripheral blood, bone marrow, and spleen [24 ]. It seems these cells cannot fully mature to monocytes, macrophages, and possibly DC as a result of the lack of the CD137 ligand signal.

The CD137 ligand provides potent activating signals to monocytes and likely monocyte precursors. As expression of CD137 is strictly activation-dependent, monocytes would encounter CD137 in tissues where activated immune cells or endothelial cells are present [36 , 37 ]. Therefore, reverse signaling by the CD137 ligand into monocytes is expected to amplify ongoing immune responses.

CD137 ligand activities on DC
The CD137 ligand is expressed at low levels on murine and human DC in vitro, derived from monocytes or hematopoietic progenitor cells or isolated from tonsil or spleen, but its expression is enhanced by proinflammatory stimuli, including IL-1, CD40 ligand, LPS, and dsRNA (Table 2) .

Cross-linking of the CD137 ligand enhances the expression of CD11c, CD80, CD86, and MHC class II and induces cellular adherence and the release of IL-6 and IL-12 [13 , 18 , 19 ]. Reports differ on whether the CD137 signal alone is sufficient or only works in combination with additional activating signals such as the CD40 ligand. It is interesting that the CD137 ligand signal also up-regulates CD137 ligand expression, pointing to a positive-feedback loop [18 ].

These activities on DC are similar to CD137 activities on monocytes. The physiological function of the CD137 ligand signal in DC is an induction or enhancement of their antigen-presenting capacity and consequently, an initiation or enhancement of immune responses.

CD137 ligand activities on B cells
B cells, another group of APC, can also express the CD137 ligand. Human and murine transformed B cells express CD137 ligand protein constitutively, and activation may be required for primary B cells (Table 2) .

Unlike in the case of monocytes, signals through the CD137 ligand do not initiate activation of B cells. Rather, they enhance proliferation and Ig synthesis of preactivated B cells [20 , 21 ]. In contrast to these in vitro data, constitutive expression of the CD137 ligand on APC in transgenic mice causes the elimination of peripheral B cells [17 ]. The CD137 ligand-transgenic mice have normal B cell numbers and function up to the age of 3 months, and develop B cell deficiencies only later in life. This could indicate that initially, the signals through the CD137 ligand are activating for B cells, and prolonged CD137 ligand signals may be deleterious for B cell numbers and functions, possibly as a result of 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 cross-linking of CD137 on monocytes causes them to induce apoptosis in B cells [38 ].

These functional data on CD137 ligand-mediated B cell activation are supported by histological findings. CD137 is expressed by follicular DC in germinal centers [20 , 39 ]. B cells accumulate after the first antigen encounter in these anatomical structures and undergo the process of affinity maturation. Follicular DC present the antigens in the 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 DC allows CD137 to provide costimulatory and survival signals to those B cells, which have rearranged their Ig genes, resulting in a high-affinity binding to the antigen [20 ].

The activities of CD137 and its ligand in B cell activation and development are reminiscent of those of the CD40 receptor/ligand pair which are also members of the TNFR 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 DC, and here, costimulation is mediated, at least in part, by the CD137 receptor/ligand system.

CD137 ligand activities on bone marrow cells
Expression of the CD137 ligand on murine bone marrow cells has been documented at the mRNA level, and CD137 ligand signaling takes place, not only in differentiated hematopoietic cells but also in bone marrow cells. Proliferation of murine bone marrow cells treated with M-CSF is enhanced when the cells are exposed to immobilized CD137 protein. CD137 ligand signals also inhibit receptor activator of nuclear factor (NF)-{kappa}B (RANK) ligand-induced differentiation of bone marrow cells toward osteoclasts [25 ]. As mentioned above, a missing differentiation signal may also be the cause for the amplification of myeloid progenitors in CD137 ligand-deficient mice [24 ]. Taken together, these data suggest that the CD137 ligand directs differentiation of bone marrow cells away from osteoclasts and into the myeloid lineage.

CD137 ligand activities on T cells
Expression of CD137 ligand protein could not be detected on primary T cells or only at low levels. However, the CD137 ligand is present on human and murine T cell lines (Table 2) . It may be that the 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 the CD137 ligand on T cells stand in contrast with those on APC and those of CD137 on T cells. The signal through the CD137 ligand down-regulates T cell activity. Coculture of anti-CD3-activated human peripheral blood mononuclear cells with CD137-transfected Chinese hamster ovary 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, and it is inactive when added as a soluble protein, demonstrating also for T cells that these effects are mediated by cross-linking the CD137 ligand [16 , 22 ].

The inhibitory effect of the 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 [24 ]. At present, it is open whether CD137 exerts this inhibitory effect directly by cross-linking the 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 the CD137 ligand are inhibitory. CD95 and CD95 ligand, two other members of the TNFR 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 the CD95 ligand is costimulatory [40 ].

When considering the T cell inhibitory effects of the CD137 ligand, it should be kept in mind that CD137 can be expressed as a neoantigen on carcinoma cells [41 ]. It may be that ectopic CD137 expression helps the tumor cells to fend off an anti-tumor immune response by inducing apoptosis in infiltrating T cells.

Not much is known about the underlying mechanism of the T cell inhibitory activities of the CD137 ligand. Although the CD137 ligand induces expression of CD95 on CD4- and CD8-positive T cells and on B cells, induction of apoptosis does not seem to involve CD95 [23 ]. For one, antagonistic CD95 antibodies do not block CD137 ligand-induced apoptosis, and second, the CD137 ligand induces apoptosis in resting as well as activated lymphocytes, while CD95-induced apoptosis is restricted to activated lymphocytes. Also, apoptosis signals through the CD137 ligand are less potent and have a slower kinetic than apoptosis signals through CD95, taking days rather than hours until apoptosis is significantly noticeable [22 , 23 ].

What could be the physiological function of the inhibitory activities of the CD137 ligand on T cells? No studies have been reported addressing this question. It may be that the CD137 ligand provides a negative feed-back 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 the CD137 ligand would also increase. As long as the antigen is present, activated APC will express the CD137 ligand and other costimulatory molecules, and T cells may receive more growth-promoting than inhibitory signals. However, when the antigen has been cleared, APC will no longer provide costimulation, and the inhibitory activities of the CD137 ligand may become predominant, thereby contributing to the downsizing of a no-longer needed, antigen-specific T cell response.

CD137 ligand activities on nonhematopoietic cells
CD137 ligand expression could be detected on human carcinoma cell lines of colon, lung, breast, ovarian, and prostate origin (Table 2) . Cross-linking of the CD137 ligand induces release of IL-8 from tumor cells [26 ]. It is, at present, not known whether the CD137 ligand is also present on the corresponding, healthy tissues or whether the tumor cells acquire CD137 ligand expression during the transformation process. It used to be puzzling why tumor cells would express the CD137 ligand, which has been shown to induce an anti-tumor immune response upon transgenic expression on tumor cells [42 , 43 ]. Further, IL-8, which is a proinflammatory chemokine and is induced by reverse signaling through the CD137 ligand, is also expected to enhance an anti-tumor immune response. However, recently, it has become evident that CD137 not only costimulates T cell activity but under certain circumstances, can inhibit T cell activity and immune responses [reviewed in ref. 6 and 44 , 45 ]. It is possible that the local environment in the tumor favors the inhibitory over the costimulatory activity of CD137 on T cells. The anti-tumor activity of infiltrating T cells would then be blocked by the tumor-expressed CD137 ligand. Thus, expression of the CD137 ligand, possibly as a neoantigen, may allow tumor cells to escape from immunosurveillance.

CD137 ligand signal transduction pathway
Signal transduction pathways involved in reverse signaling through the CD137 ligand have been studied using M-CSF or RANK ligand-induced osteoclast differentiation of murine bone marrow cells. The CD137 ligand signal suppressed phosphorylation of Akt, whereas it had no effect on the phosphorylation of inhibitor of receptor activator of NF-{kappa}B and extracellular signal-regulated kinase 1/2, p38, and jun kinase. The CD137 ligand signal also suppressed NF of activated T cells-2 induction but did not affect the expression of TNFR-associated factor 6 and c-Fos. Casein kinase (CK) is also implicated in CD137 ligand signaling, as its inhibition blocked CD137 ligand-mediated osteoclast differentiation and proliferation of bone marrow cells [25 ]. A recognition site for CK is present in the cytoplasmic domain of the CD137 ligand [46 ].

Is reverse CD137 signaling real?
Sometimes the concept of reverse signaling is still being met with skepticism, and it is being questioned whether the observed effects cannot be explained otherwise. The quantity of data contributed by a number of different laboratories makes incidental findings highly unlikely. Also, identical results are obtained when recombinant CD137 protein, anti-CD137 ligand antibodies, or CD137-transfected cells are used to activate the CD137 ligand, ruling out the possibility that observed effects may be a result of contaminations in protein batches. Also, the phenotypes of CD137 ligand-transgenic and CD137-deficient mice confirm the data obtained in vitro. In addition, a signaling cascade initiating from the cytoplasmic domain of the CD137 ligand is being identified. These independent lines of evidence form a solid basis for the acceptance of reverse signaling through the CD137 ligand.


   PERSPECTIVE
TOP
 ABSTRACT
 SCOPE OF THIS REVIEW
 CD137 REVERSE SIGNALING
 PERSPECTIVE
SUMMARY
 REFERENCES
 
Bidirectional signaling adds considerable complexity to the biology of the CD137 receptor/ligand system. Therapeutic applications are being considered for the CD137 or CD137 ligand, and the full identification of the mechanisms underlying their activities would therefore be highly desirable.

One of the important tasks for future research will be to identify which activities are mediated by CD137 and which by CD137 ligand signaling. Studies using knockout mice or antagonists, such as antibodies or soluble receptors, are not expected to bring clarity, as they inhibit signaling in both directions. However, CD137 and CD137 ligand mutants lacking the cytoplasmic domains would disrupt signaling in only one direction. As a result of trimerization of CD137 and its ligand, truncated forms of these molecules should also exert a dominant-negative effect and inactivate intact forms of CD137 and CD137 ligand, respectively.

CD137 has been reported to costimulate as well as to inhibit T cell activity. It is, at present, not yet clear how these opposite functions of CD137 are regulated and in which situations they are used. It would however be interesting to determine whether the inhibitory effects of the CD137 ligand and CD137 on T cells are coordinated and used simultaneously. If that were the case, this would open up the possibility of fratricide through CD137 and CD137 ligand, as has already been documented for the CD95 receptor/ligand system [47 ].


   SUMMARY
TOP
 ABSTRACT
 SCOPE OF THIS REVIEW
 CD137 REVERSE SIGNALING
 PERSPECTIVE
 SUMMARY
REFERENCES
 
The signal through the CD137 ligand is activating or costimulatory for APC (Table 1) . Together with CD137, which can deliver costimulatory signals to T cells, the CD137 receptor/ligand pair can form a potent, proinflammatory system, enhancing immune reactions by stimulating APC as well as T cells. The CD137 ligand, however, negatively regulates T cell proliferation and survival, and it is possible that this activity of the CD137 ligand plays a role at the end of an immune response when the antigen has been cleared, and the number of antigen-specific T cells gets reduced (Table 1) . This T cell-inhibitory activity of the CD137 ligand on T cells may be used by tumors, which can express CD137 as a neoantigen, to defend themselves against a host immune response. Similarly, tumor cells may express the CD137 ligand, as the signal through CD137 is not necessarily stimulatory but can, under certain circumstances, suppress immune responses.

The reverse signaling pathways initiated by the CD137 ligand have not yet been fully elucidated, but it seems reverse signaling does not use a new set of signal transducing molecules; rather, the CD137 ligand uses molecules that are well known from the study of other signaling pathways.

It becomes increasingly evident that the CD137 receptor/ligand system mediates essential cross-talk between many leukocyte subpopulations and also between immune and nonimmune cells. The basis for this extensive cross-talk and the many diverse activities is the ability of the CD137 receptor/ligand system to transduce signals in both directions. The identification of which activities are mediated by CD137 or by CD137 ligand signaling will enhance our understanding of immunoregulation and should also be helpful in the development of therapeutics targeting the CD137 receptor/ligand system.

Received September 27, 2004; revised November 9, 2004; accepted November 11, 2004.


   REFERENCES
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 CD137 REVERSE SIGNALING
 PERSPECTIVE
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 REFERENCES
 

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