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Targeting autoantigen-specific T cells and suppression of autoimmune encephalomyelitis with receptor-modified T lymphocytes

Nature Biotechnology volume 20, pages 1215–1220 (2002)Cite this article

Abstract

We demonstrate here the feasibility of antigen-specifically redirecting T cells against autoreactive T lymphocytes and thereby treating a model autoimmune disease. We created and transgenically expressed on T cells a heterodimeric chimeric receptor that genetically links an autoantigenic peptide, its restricting MHC, and the signal transduction domain of the T-cell receptor (TCR) ζ-chain. Engagement of the chimeric receptor by the TCR of autoreactive T cells activated the receptor-modified T cells in vitro and in vivo, inducing proliferation and cytolysis. Adoptively transferred receptor-modified T cells prevented and treated a model autoimmune disease, experimental allergic encephalomyelitis (EAE), even after epitope spreading had diversified the autoantigenic response. Treatment reduced disease severity and increased survival of affected animals, and was durable for >75 days. The receptor-modified cells acted both by strongly attenuating T-cell response to autoantigen as well as by shifting the residual response from an immunopathologic Th1 to a protective Th2 format.

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Figure 1: Chimeric receptor expression on T lymphocytes.
Figure 2: Stimulation of 25S89P T cells by cognate TCR.
Figure 3: Proliferation of 25S89P T cells in response to MBP89–101-specific T cells in vivo.
Figure 4: Prevention and treatment of EAE by 25S89P T cells.
Figure 5: Treatment of EAE with 25S89P T cells after epitope spread.
Figure 6: Suppression of autoantigen-specific T-cell response and cytokine shift after treatment with receptor-modified T cells.

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Acknowledgements

The authors thank Richard Cross, Dick Ashmun, and Mahnaz Paktinat for assistance with flow cytometry and cell sorting, Phuong Nguyen for assistance with mouse phenotyping, and D. Kioussis for providing the phCD2-VA expression vector. This work is supported by NIH grants AI01480 and AI49872 (T.L.G.), the American Lebanese Syrian Associated Charities (T.L.G., M.D.J.), and the Howard Hughes Medical Institute (R.A.F.).

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Authors and Affiliations

  1. Department of Pathology, St. Jude Children's Research Hospital, 332 N. Lauderdale Street, Memphis, 38105, TN

    M. Divya Jyothi & Terrence L. Geiger

  2. Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, 310 Cedar Street, FMB 412, New Haven, 06520, CT

    Richard A. Flavell

  3. Department of Pathology, University of Tennessee School of Medicine, 899 Madison Avenue, Memphis, 38163, TN

    Terrence L. Geiger

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  1. M. Divya Jyothi
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Correspondence to Terrence L. Geiger.

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Jyothi, M., Flavell, R. & Geiger, T. Targeting autoantigen-specific T cells and suppression of autoimmune encephalomyelitis with receptor-modified T lymphocytes. Nat Biotechnol 20, 1215–1220 (2002). https://doi.org/10.1038/nbt758

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