Single-cell transcriptomics reveal that PD-1 mediates immune tolerance by regulating proliferation of regulatory T cells

Genome Medicine

Yuk Ming Dennis Lo¹  Xisheng Li¹  Kevin Y. Yang¹  Jason C. H. Tsang¹  Kathy O. Lui¹  Vicken W. Chan¹  Cherry S. Leung¹  Manching Ku²  Shohei Hori³  Herman Waldmann⁴ 

[1] Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong;Department of Paediatrics and Adolescent Medicine, Division of Paediatric Hematology and Oncology, Faculty of Medicine, Medical Center, University of Freiburg;Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo;Sir William Dunn School of Pathology, University of Oxford;

关键词: Single-cell transcriptomics;    Transplant tolerance;    CD4+ regulatory T cells;    PD-1;    Human pancreatic beta cells;   

DOI  :  10.1186/s13073-018-0581-y

来源: DOAJ

【 摘 要 】

Abstract Background We have previously reported an antigen-specific protocol to induce transplant tolerance and linked suppression to human embryonic stem cell (hESC)-derived tissues in immunocompetent mice through coreceptor and costimulation blockade. However, the exact mechanisms of acquired immune tolerance in this model have remained unclear. Methods We utilize the NOD.Foxp3 hCD2 reporter mouse line and an ablative anti-hCD2 antibody to ask if CD4+FOXP3+ regulatory T cells (Treg) are required for coreceptor and costimulation blockade-induced immune tolerance. We also perform genome-wide single-cell RNA-sequencing to interrogate Treg during immune rejection and tolerance and to indicate possible mechanisms involved in sustaining Treg function. Results We show that Treg are indispensable for tolerance induced by coreceptor and costimulation blockade as depletion of which with an anti-hCD2 antibody resulted in rejection of hESC-derived pancreatic islets in NOD.Foxp3 hCD2 mice. Single-cell transcriptomic profiling of 12,964 intragraft CD4+ T cells derived from rejecting and tolerated grafts reveals that Treg are heterogeneous and functionally distinct in the two outcomes of transplant rejection and tolerance. Treg appear to mainly promote chemotactic and ubiquitin-dependent protein catabolism during transplant rejection while seeming to harness proliferative and immunosuppressive function during tolerance. We also demonstrate that this form of acquired transplant tolerance is associated with increased proliferation and PD-1 expression by Treg. Blocking PD-1 signaling with a neutralizing anti-PD-1 antibody leads to reduced Treg proliferation and graft rejection. Conclusions Our results suggest that short-term coreceptor and costimulation blockade mediates immune tolerance to hESC-derived pancreatic islets by promoting Treg proliferation through engagement of PD-1. Our findings could give new insights into clinical development of hESC-derived pancreatic tissues, combined with immunotherapies that expand intragraft Treg, as a potentially sustainable alternative treatment for T1D.

【 授权许可】

Unknown