The CD137 receptor (4-1BB, TNFRSF9) is a member of the tumor necrosis factor receptors (TNFR) family and was characterized as an inducible costimulatory receptor on T-cells, together with its ligand (CD137L, 4-1BBL), both in human and mice [
14]. CD137 was initially described as a surface marker expressed by activated T-cells, with an in vitro peak expression 48 h after the primary T-cell activation signal and a decline starting from day 4–5 [
14,
15,
16,
17]. In vivo, its expression upon activation turned out to happen even earlier, starting indeed at 12h post-immunization [
18,
19]. Both CD4
+ and CD8
+ T-cells are able to upregulate CD137, even if its expression on CD8
+ T-cells is earlier and higher [
20,
21,
22].
However, CD137 receptor is not a specific marker for T-cells, since it can be expressed, even if to a smaller extent, also by dendritic cells (DCs), monocytes, natural killer (NK) cells, eosinophils, and microglia [
23]. On the other side, CD137L is expressed by activated antigen presenting cells (APC) as macrophages, DCs, and B-cells [
20,
23,
24,
25,
26]. Therefore, it is reliable to suppose that the engagement between CD137 and its ligand is part of the complex pathways of interactions between APCs and T-cells.
Similarly to other members of the TNFR family, the CD137 receptor relies on TRAFs proteins to build its signaling [
27]. The binding of both CD137L [
28,
29] and agonistic antibodies [
30] results in a quick recruitment of TRAF1 and TRAF2 to the receptor. The consequent TRAF-mediated activation of NF-kB and MAPK intracellular signaling, leads to T-cell division and proliferation, an increased cell survival and enhanced effector functions in both CD4
+ and CD8
+ T-cells [
15]. As for CD137 expression, also TRAF1 expression is induced by T-cell activation, confirming that the CD137-induced signalosome is required for cytotoxic T-cells (CTL) expansion and for the boosting of effector functions [
27]. In fact, a number of mice experiments proved that CD137 stimulation is able to increase T-cell proliferation and cytokine production [
14,
23]. Consistently, in absence of the CD28 signal, T-cells treated with an anti-CD3 and CD137L can proliferate and produce interleukin 2 (IL-2) to a similar extent of those treated with the combination of anti-CD3 and anti-CD28, but just in the presence of a consistent antigen stimulation [
31,
32,
33,
34]. This evidence was one of the starting points to get to the notion that CD137 identifies those T-cells that are activated against a specific antigen. The CD137L stimulation of human CD8
+ T-cells leads to the expansion of this T-cells subset which is followed by an increase of effector molecules such as granzyme A, interferon ɣ (IFN-ɣ), perforin, and different cytokines, driving CD8
+ memory T-cells toward a differentiated effector phenotype [
35,
36]. In addition, the CD137 receptor seems to have a strong and prevalent role in increasing T-cell survival by preventing activation-induced T-cell death [
37,
38] and this appears to be in line with the physiological timing of the CD137 signal that is subsequent to the TCR and CD28 mediated signals. The BIM downregulation and the induction of Bcl-XL and Bfl-1 were pointed out as responsible for the inhibition of the activation-induced cell death, after the CD137 engagement [
39]. Further studies also showed that the CD137 engagement is able to stimulate the mitochondrial metabolism in order to increase T-cell respiratory capacities [
40,
41] and to induce DNA demethylation in CD8
+ T-cells main genes and chromatin reprogramming [
42]. As above mentioned, different studies highlighted a preferential role of CD137 in CD8
+ T cells rather than in CD4
+ T cells, even if it can be induced on both the T-cell subsets, including CD4
+ regulatory T-cells (Tregs) [
43]. However, the effective function of CD137 signaling on CD4
+ T-cells is still unclear and may thus not be as physiologically relevant as for CD8
+ T cells [
44].As confirmation, mice deficient for CD137 show an impaired antiviral response mediated by CD8
+ T cells [
45,
46,
47]. Similarly, mice deficient for CD137L that were adoptively transferred with OT-1 derived CD8
+ T-cells, showed a marked reduction of these OVA-specific T-cells in both the late primary response and the secondary expansion to OVA/LPS [
19]. Moreover, when anti-CD137 monoclonal antibodies or CD137L injections were tested in cancer therapy, a significant benefit in terms of antitumor response was noticed [
21,
24,
38,
48,
49,
50,
51,
52,
53,
54,
55,
56,
57]. When CD137 was targeted by in vivo treatments with an agonistic anti-CD137 monoclonal antibody, it resulted in an increased effect on CD8
+ T-cells expansion and activation with just a modest effect on CD4
+ T-cells, thus confirming that in vivo its signal affects predominantly this subset of T-cells [
50,
58].