Kennedy, Waters, and Rowshanravan et al. showed that CTLA-4 captured its tagged ligands from opposing cells to mediate transendocytosis (TE) into CTLA-4+ cells. CD86 dissociated from CTLA-4 in a pH-dependent manner to enable CTLA-4 recycling, whereas CD80 stayed bound to CTLA-4, which was ubiquitylated and trafficked via late endosomes/lysosomes to prevent CTLA-4 recycling. CTLA-4 recycling defects due to CD86 TE disruption caused by deficiency of a key protein trafficking regulator, LRBA protein, or by specific CTLA-4 mutations led to T cell dysregulation in vitro, and associated with clinical autoimmunity.
Contributed by Paula Hochman
ABSTRACT: CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both receptors share the same ligands, CD80 and CD86, the specific requirement for two distinct ligands remains obscure. In the present study, we demonstrate that, although CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, this process results in separate fates for CTLA-4 itself. In the presence of CD80, CTLA-4 remained ligand bound, and was ubiquitylated and trafficked via late endosomes and lysosomes. In contrast, in the presence of CD86, CTLA-4 detached in a pH-dependent manner and recycled back to the cell surface to permit further transendocytosis. Furthermore, we identified clinically relevant mutations that cause autoimmune disease, which selectively disrupted CD86 transendocytosis, by affecting either CTLA-4 recycling or CD86 binding. These observations provide a rationale for two distinct ligands and show that defects in CTLA-4-mediated transendocytosis of CD86 are associated with autoimmunity.
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) UCL Institute of Immunity and Transplantation, London, UK. (8) Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK. (9) UCL Institute of Immunity and Transplantation, London, UK. (10) UCL Institute of Immunity and Transplantation, London, UK. (11) UCL Institute of Immunity and Transplantation, London, UK. (12) School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, UK. (13) Celentyx Ltd, Birmingham, UK. (14) UCL Institute of Immunity and Transplantation, London, UK. (15) Division of Structural Biology, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan. (16) Medical Research Council Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK. (17) Structural Biology, The Rosalind Franklin Institute, Didcot, UK. Division of Structural Biology, University of Oxford, Oxford, UK. Wellcome Trust Centre for Human Genetics, Oxford, UK. Protein Production UK, The Rosalind Franklin Institute-Diamond Light Source, The Research Complex at Harwell, Didcot, UK. (18) Medical Research Council Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK. Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (19) Institute of Structural and Molecular Biology, University College London, London, UK. (20) UCL Institute of Immunity and Transplantation, London, UK. (21) UCL Institute of Immunity and Transplantation, London, UK. d.sansom@ucl.ac.uk.
