4-1BB Ligand-Mediated Costimulation of Human T Cells Induces CD4 and CD8 T Cell Expansion, Cytokine Production, and the Development of Cytolytic Effector Function

Abstract

4-1BB (CD137) is a costimulatory member of the TNFR family expressed on activated T cells. Its ligand, 4-1BBL, is expressed on activated APC. In the mouse, CD8 T cells are preferentially activated by agonistic anti-murine 4-1BB Abs. However, murine 4-1BBL can stimulate both CD4 and CD8 T cells. To date, there are only limited data on the effects of 4-1BBL on human T cell responses. To further understand the role of 4-1BBL in human T cell responses, we compared human CD4 and CD8 T cell responses to transfected human 4-1BBL plus TCR-mediated stimulation. Both human CD4 and CD8 T cells responded to 4-1BBL. The presence of 4-1BBL on the APC led to increased expansion, cytokine production, and the development of cytolytic effector function by human T cells. In unfractionated T cell cultures, CD4 and CD8 T cells could expand to a similar extent in response to signals through the TCR and 4-1BB, as measured by CFSE labeling and by quantitating T cell numbers in the cultures. In contrast to the results with total T cells, isolated CD8 T cells produced less IL-2 and expanded to a lesser extent than isolated CD4 T cells responding to 4-1BBL. Thus, 4-1BBL is most effective when both CD4 and CD8 T cells are included in the cultures. CD28 and 4-1BB were found to synergize in the induction of IL-2 by human T cells, and CTLA-Ig partially blocked 4-1BBL-dependent IL-2 production. However, a portion of the 4-1BBL-mediated effects were independent of CD28-B7 interaction.

Massive parallel screening of phage libraries for the generation of repertoires of human immunomodulatory monoclonal antibodies

“…Other co-stimulatory proteins that are considered good targets for antibody-mediated immunotherapy are inducible T cell costimulator (ICOS), which is an immune checkpoint protein belonging to the CD28-superfamily that is expressed on activated T cells, and CD27, a member of the tumor necrosis factor receptor superfamily, which is required for generation and long-term maintenance of T cell immunity. 13-15 …”

Enhancement of CD4 and CD8 immunity by anti-CD137 (4-1BB) monoclonal antibodies during hepatitis C vaccination with recombinant adenovirus

“…A single ligand for CD137 has been identified whose expression has been found on activated dendritic cells, B cells and macrophages [27][28][29][30]. There is ample evidence that CD137 driven signals are potent for CD8 + T cell stimulation [23,[31][32][33][34][35][36][37][38][39][40] and if provided together with those signals from CD28 and TCR, the T lymphocytes reach optimal levels of activation [23,34,38,39]. Thus, treatments with agonistic anti-CD137 monoclonal antibodies have shown to induce potent CTL-mediated antitumor effects [31,41] synergizing with tumor antigen immunization [41,42].…”

Targeting LFA-1 Synergizes with CD40/CD40L Blockade for Suppression of Both CD4-Dependent and CD8-Dependent Rejection

“…These include inducible costimulatory molecule ICOS/B7H (12)(13)(14), 4-1BB/4-1BB ligand (4-1BBL) (15)(16)(17)(18)(19)(20), OX40/OX40 ligand (OX40L) (21,22), LIGHT and herpesvirus entry mediator (HVEM) or lymphotoxin b receptor (LTbR), and membrane lymphotoxin (mLT)/LTbR (mLT/LTbR) interactions (23,24).…”