Bidirectional signaling provides considerable complexity to the biology of the CD137 receptor/ligand system. Reverse signaling feeds back to the CD137 ligand-expressing cells and allows a more coordinated immune response and its fine-tuning.
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 knock-out mice or antagonists, such as antibodies are not expected to bring clarity since they inhibit signaling in both directions. However, CD137 and CD137 ligand mutants lacking the cytoplasmic domains would disrupt signaling in only one direction. Due to trimerization of CD137 and its ligand, truncated forms of these molecules should also exert a dominant negative effect and inactivate trimers of intact CD137 and CD137 ligand, respectively. Alternatively, once the signal transduction pathways of CD137 and CD137 ligand have been elucidated it may be possible to use inhibitors which block only one of the two pathways. The reverse signaling pathways initiated by CD137 ligand has only been partly elucidated, but it seems reverse signaling does not employ a new set of signal transducing molecules, rather, CD137 ligand signaling relies on molecules which are well known from the study of other signaling pathways.
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 utilized. It would however be interesting to determine whether the inhibitory effects of CD137 ligand and CD137 on T cells are coordinated and employed 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 (Callard et al., 2003).
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 CD137 ligand, ruling out the possibility that observed effects may be due to 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 CD137 ligand is being identified. These independent lines of evidence form a solid basis for the acceptance of reverse signaling through CD137 ligand.
It becomes increasingly evident that the CD137 receptor/ligand systemmedi-ates essential cross talk between many leukocyte subpopulations, and also between immune and non-immune cells. The basis for this extensive cross talk and 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 the regulation of immune responses, and should also be helpful in the development of therapeutics targeting the CD137 receptor/ligand system.
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