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

Genome Medicine
Cherry S LeungKathy O Lui

Abstract

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. We utilize the NOD.Foxp3hCD2 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. 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.Foxp3hCD2 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...Continue Reading

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Citations

Jul 3, 2020·Journal for Immunotherapy of Cancer·Thilo GambichlerJürgen Christian Becker
Nov 7, 2019·Current Diabetes Reports·Marina BakayHakon Hakonarson
Jul 4, 2020·Current Opinion in Endocrinology, Diabetes, and Obesity·Adeeb H Rahman, Dirk Homann
May 1, 2020·International Journal of Endocrinology·Xue ZhangHaixia Liu

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Methods Mentioned

BETA
scRNA-seq
FACS
PCR
Chips
flow cytometry
RNA-seq
ubiquitination
intragraft

Software Mentioned

STAR
DAVID Bioinformatics Resources
sSeq
Qubit
Scran
SNE
FlowJo
Cell Ranger
Cell Ranger Single - Cell Software Suite
HOMER

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