Date: December 9, 2021
Time: 8:00am (PDT), 11:00am (EDT)
Engineering human regulatory T cells (Tregs) with a chimeric antigen receptor (CAR) targeting donor-derived human leukocyte antigen (HLA) is a promising strategy to induce immune tolerance to pancreatic islet transplants, the only curative procedure available for type 1 diabetes. Here, we describe a novel anti-HLA-A2 CAR (A2-CAR) created by grafting the complementarity-determining regions (CDRs) of a human monoclonal anti-HLA-A2 antibody into the Herceptin 4D5 single-chain variable fragment and fusing it to a CD28-zeta signaling domain. A2-CAR Tregs were generated either by ablating the endogenous T-cell receptor (TCR) constant region alpha (TRAC) locus via CRISPR/Cas9 and then introducing the A2-CAR by lentiviral transduction, or by directly knocking the A2-CAR gene into the TRAC locus. A2-CAR+TCR- human Tregs maintained Treg phenotype and function in vitro. Moreover, they selectively accumulated in HLA-A2-expressing islets transplanted from either HLA-A2 transgenic mice or deceased human donors into immunodeficient mice. Importantly, A2-CAR+TCR- Tregs did not impair the function of these HLA-A2+ islets, whereas A2-CAR+TCR-CD4+ T effector cells rejected HLA-A2+ islets in less than 2 weeks. In addition, A2-CAR+TCR- Tregs delayed xenogeneic graft-versus-host disease specifically in the presence of HLA-A2 antigen in co-transferred peripheral blood mononuclear cells, the recipient mice, or both. In summary, genome-engineered human A2-CAR Tregs localize to HLA-A2-expressing islet grafts and exhibit antigen-dependent in vivo suppression, independent of TCR expression. This work may inform the development of precision Treg cell-based strategies to assuage islet transplant rejection.
- What are regulatory T cells?
- What is a chimeric antigen receptor?
- What are the challenges treating autimmune disease and organ transplant rejection?
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