No evidence for dualism in function and receptors: PD‐L2/B7‐DC is an inhibitory regulator of human T cell activation

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Abstract
The B7 family member programmed‐death‐1‐ligand 2 (PD‐L2/B7‐DC) is a ligand for programmed‐death‐receptor 1 (PD‐1), a receptor involved in negative regulation of T cell activation. Several independent studies have reported that PD‐L2, however, can also potently costimulate murine T cells via an additional yet unidentified receptor. In this study, we evaluated the contribution of PD‐L2 to the activation of human T cells using a novel system of engineered T cell stimulators that expresses membrane‐bound anti‐CD3 antibodies. Analyzing early activation markers, cytokine production and proliferation, we found PD‐L2 to consistently inhibit T cell activation. PD‐L2 inhibition affected CD4+ and CD8+ T cells and was not abrogated by costimulation via CD28. Blocking PD‐1 reverted the inhibitory effect of PD‐L2, demonstrating involvement of this pathway. In human T cells, we found no evidence for any of the costimulatory effects described for PD‐L2 in murine systems. In line with our functional data that do not point to stimulatory PD‐L2‐ligands, we show that binding of PD‐L2‐immunoglobulin to activated human T cells is abrogated by PD‐1 antibodies. Our results demonstrate that PD‐L2 negatively regulates human T cell activation and thus might be a candidate molecule for immunotherapeutic approaches aimed to attenuate pathological immune responses.