Characterization of CD137 Ligand mediated human monocyte differentiation and their effects on T cell activities

Abstract

CD137 is a member of the tumour necrosis factor receptor (TNFR) superfamily that is expressed on a variety of immune cells. Its activation provides co-stimulatory signals to T cells and preferentially induces proliferation and activation of CD8 T cells. Similar to CD137, its ligand (CD137L), is also a membrane bound protein. Interaction between CD137 and CD137L not only induces signalling into the receptor bearing cell, it also initiates signalling into the ligand bearing cell. Hence, CD137 and its ligand participate in bidirectional signalling and stimulation of CD137L which results in signalling into ligand bearing cells has been termed as CD137 reverse signalling.

In human monocytes, CD137L signalling delivers a potent activating signal. However, characterization of monocyte activation by CD137L has been restricted to the production of pro-inflammatory cytokines, adherence and morphological changes. This study shows that treatment of monocytes with recombinant CD137 protein, which stimulates CD137L on monocytes, also induces their differentiation to dendritic cells (DCs). This is evidenced by the increased endocytic capacity, up-regulation of co-stimulatory molecules and the ability to induce proliferation of naïve T cells. CD137 not only induces monocyte to DC differentiation but also promotes DC maturation. These DCs in turn inhibit development of regulatory T cells but induce T cell expression of perforin, IFN-g, IL-13 and IL-17 and T cells with a high killing activity. Hence, recombinant CD137 protein as a sole factor can induce differentiation of monocytes to mature, inflammatory DCs that have a potent T cell stimulatory capacity. As such, CD137 show potential in generating DCs that can be used in human immunotherapy.

In contrast to these T cell stimulatory activities, CD137L stimulated monocytes also induce T cell apoptosis. CD137 mediated, monocyte dependent T cell apoptosis requires direct cell to cell contact and occurs independently of the extrinsic pathway of apoptosis. Instead, ROS are implicated in mediating T cell apoptosis. Hence, this study shows two contrasting activities of CD137L stimulated monocytes that are temporally separated; early induction of T cell apoptosis that is followed by its T cell stimulatory function.

The pattern of CD137 induced, monocyte dependent T cell apoptosis show close similarities to infection induced T cell attrition which occurs during a number of viral infections. This early T cell apoptosis is suggested to be beneficial to the subsequent development of pathogen specific immune responses by (1) creating space in the lymphoid organ for expansion of antigen specific T cells and (2) depleting low affinity cross reactive T cells that can impede the development of proper immune responses. Hence, the two phases of CD137L mediated monocyte activation seem to be geared towards the development of an inflammatory immune response.