Kennedy, Robinson, and Hinze et al. showed that despite the interaction between CD80 and PD-L1 on the cell surface of APCs, T cell CTLA-4 regulates the levels of CD80 while maintaining the levels of PD-L1. The cytoplasmic domain of CTLA-4 promoted effective time-dependent depletion of CD80 and CD86, but not the associated PD-L1, via transendocytosis, which efficiently liberated PD-L1 over time to functionally engage PD-1 and inhibit TCR signaling. CTLA-4 binding to CD80 alone was insufficient for effective PD-L1 release.
Contributed by Shishir Pant
ABSTRACT: CTLA-4 and PD-1 are key immune checkpoint receptors that are targeted in the treatment of cancer. A recently identified physical interaction between the respective ligands, CD80 and PD-L1, has been shown to block PD-L1/PD-1 binding and to prevent PD-L1 inhibitory functions. Since CTLA-4 is known to capture and degrade its ligands via transendocytosis, we investigated the interplay between CD80 transendocytosis and CD80/PD-L1 interaction. We find that transendocytosis of CD80 results in a time-dependent recovery of PD-L1 availability that correlates with CD80 removal. Moreover, CD80 transendocytosis is highly specific in that only CD80 is internalised, while its heterodimeric PD-L1 partner remains on the plasma membrane of the antigen-presenting cell (APC). CTLA-4 interactions with CD80 do not appear to be inhibited by PD-L1, but efficient removal of CD80 requires an intact CTLA-4 cytoplasmic domain, distinguishing this process from more general trogocytosis and simple CTLA-4 binding to CD80/PD-L1 complexes. These data are consistent with CTLA-4 acting as modulator of PD-L1:PD-1 interactions via control of CD80.
Author Info: (1) UCL Institute of Immunity and Transplantation, London, UK. (2) UCL Institute of Immunity and Transplantation, London, UK. (3) UCL Institute of Immunity and Transplantation, Lon
Author Info: (1) UCL Institute of Immunity and Transplantation, London, UK. (2) UCL Institute of Immunity and Transplantation, London, UK. (3) UCL Institute of Immunity and Transplantation, London, UK. (4) UCL Institute of Immunity and Transplantation, London, UK. (5) UCL Institute of Immunity and Transplantation, London, UK. (6) UCL Institute of Immunity and Transplantation, London, UK. (7) Early Oncology R&D, AstraZeneca, UK. (8) UCL Institute of Immunity and Transplantation, London, UK.
