Antibody‐mediated signaling through PD‐1 costimulates T cells and enhances CD28‐dependent proliferation

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Abstract
Programmed death‐1 (PD‐1, CD279) is a molecule expressed on activated T, B and myeloid cells. The role of the interaction of PD‐1 ligands (PD‐L1 and PD‐L2) with PD‐1 receptor and the type of signals (costimulatory or inhibitory) that are delivered is a subject of intense debate. Our study has characterized two monoclonal antibodies (mAb) against murine PD‐1, termed clone 1H10 and clone 4F10, that recognized different epitopes from that of anti‐PD‐1, clone J43. We showed that neither of them inhibited anti‐CD3‐mediated proliferation, but 1H10 mAb induced direct T cell proliferation in the absence of any other stimulus. Moreover, PD‐1 engagement with 1H10 mAb costimulated anti‐CD3‐mediated proliferation and enhanced anti‐CD3/CD28 proliferation on both CD4+ and CD8+ T cells in the low range of anti‐CD3 concentrations. Anti‐PD‐1‐mediated proliferation induced with 1H10 mAb was also observed in vivo on CD4+ and CD8+ T cells, when CFSE‐labeled splenocytes were adoptively transferred to irradiated syngeneic and allogeneic recipients. Overall, our data indicate that PD‐1 might not only deliver negative signals to T cells upon interaction through one of its ligands, PD‐L1 as reported, but also could costimulate T cells, suggesting a dual potential functional activity of the extracellular domains of this receptor.