CD137 is expressed on activated T cells and NK cells, among others, and is a potent co-stimulator of antitumor immune responses. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC), and CD137L reverse signaling into APC enhances their activity. CD137-CD137L interactions as main driver of type 1, cell-mediated immune responses explains the puzzling observation that CD137 agonists which enhance antitumor immune responses also ameliorate autoimmune diseases. Upon co-stimulation by CD137, Th1 CD4 T cells together with Tc1 CD8 T cells and NK cells inhibit other T cell subsets, thereby promoting antitumor responses and mitigating non-type 1 auto-immune diseases.

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Therapeutic tumor vaccination based on dendritic cells (DC) is safe; however, its efficacy is low. Among the reasons for only a subset of patients benefitting from DC-based immunotherapy is an insufficient potency of in vitro generated classical DCs (cDCs), made by treating monocytes with GM-CSF + IL-4 + maturation factors. Recent studies demonstrated that CD137L (4-1BBL, TNFSF9) signaling differentiates human monocytes to a highly potent novel type of DC (CD137L-DCs) which have an inflammatory phenotype and are closely related to in vivo DCs. Here, we show that CD137L-DCs induce potent CD8 T-cell responses against Epstein-Barr virus (EBV) and Hepatitis B virus (HBV), and that T cells primed by CD137L-DCs more effectively lyse EBV and HBV target cells. The chemokine profile of CD137L-DCs identifies them as inflammatory DCs, and they polarize CD8 T cells to a Tc1 phenotype. Expression of exhaustion markers is reduced on T cells activated by CD137L-DCs. Furthermore, these T cells are metabolically more active and have a higher capacity to utilize glucose. CD137L-induced monocyte to DC differentiation leads to the formation of AIM2 inflammasome, with IL-1beta contributing to CD137L-DCs possessing a stronger T cell activation ability. CD137L-DCs are effective in crosspresentation. PGE2 as a maturation factor is required for enhancing migration of CD137L-DCs but does not significantly reduce their potency. This study shows that CD137L-DCs have a superior ability to activate T cells and to induce potent Tc1 responses against the cancer-causing viruses EBV and HBV which suggest CD137L-DCs as promising candidates for DC-based tumor immunotherapy.

CD137 ligand (CD137L) is expressed on APCs and crosslinks CD137, a powerful costimulatory molecule on T cells during cognate interactions, and thereby greatly enhances immune responses. We report that CD137 can be transferred from activated T cells and from tumor cells that express CD137 to other cells via trogocytosis. This trogocytic transfer is independent of CD137L expression by the recipient cell. However, if CD137L is present on the recipient cell, the transferred CD137 binds to CD137L and the CD137-CD137L complex becomes internalized. The removal of CD137L from the surface of APCs lowers their ability to costimulate T cells, as evidenced by a reduced IFN-γ secretion. Removal of CD137L on APCs by trogocytic transfer of CD137 occurs within 1 h and requires cell-cell contact and the continuous presence of CD137-expressing cells. Bidirectional signaling exists for the CD137 receptor/ligand system, because CD137L also signals into APCs. We propose that the trogocytic transfer of CD137 from activated T cells to APCs and the subsequent removal of CD137L from APCs is a physiologic regulatory mechanism that limits immune activity. Furthermore, we hypothesize that the trogocytic transfer of CD137 occurs in cancers and quenches the activity of APCs, contributing to the cancer cells escaping immune surveillance. Taken together, our findings demonstrate that the trogocytic transfer of CD137 leads to an internalization of CD137L on APCs and a reduction in immune activity.