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BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1

Nature Immunology volume 4, pages 670–679 (2003)Cite this article

Abstract

During activation, T cells express receptors for receiving positive and negative costimulatory signals. Here we identify the B and T lymphocyte attenuator (BTLA), an immunoglobulin domain–containing glycoprotein with two immunoreceptor tyrosine-based inhibitory motifs. BTLA is not expressed by naive T cells, but it is induced during activation and remains expressed on T helper type 1 (TH1) but not TH2 cells. Crosslinking BTLA with antigen receptors induces its tyrosine phosphorylation and association with the Src homology domain 2 (SH2)-containing protein tyrosine phosphatases SHP-1 and SHP-2, and attenuates production of interleukin 2 (IL-2). BTLA-deficient T cells show increased proliferation, and BTLA-deficient mice have increased specific antibody responses and enhanced sensitivity to experimental autoimmune encephalomyelitis. B7x, a peripheral homolog of B7, is a ligand of BTLA. Thus, BTLA is a third inhibitory receptor on T lymphocytes with similarities to cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1).

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Figure 1: BTLA sequence and genomic structure.
Figure 2: Expression of BTLA in lymphoid cells.
Figure 3: BTLA is transmembrane, glycoslyated, and tyrosine-phosphorylated on induction.
Figure 4: Inducible association of BTLA with SHP-2.
Figure 5: Generation and analysis of BTLA-deficient mice.
Figure 6: In vitro responses of BTLA-deficient lymphocytes.
Figure 7: Increased EAE susceptibility in BTLA-deficient mice.
Figure 8: Infiltration of the CNS in MOG-induced EAE in BTLA-deficient mice.
Figure 9: BTLA interacts with an orphan B7 B7x.

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Acknowledgements

We thank B. Sleckman for help with gene targeting; M. White for generating chimeric mice; M. Gimenez for help with immunohistochemistry; and W. Sha for discussions. This work was supported in part by grants from the National Institutes of Health. J.P.A. and K.M.M. are Investigators of the Howard Hughes Medical Institute.

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Author notes

  1. Norihiko Watanabe

    Present address: The Second Department of Internal Medicine, Chiba University School of Medicine, J1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

  2. Jianfei Yang

    Present address: Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, Connecticut, 06877, USA

Authors and Affiliations

  1. Department of Pathology & Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, Box 8118, 660 South Euclid Avenue, St. Louis, 63110, Missouri, USA

    Norihiko Watanabe, Maya Gavrieli, John R Sedy, Jianfei Yang, Susan K Loftin, Michelle A Hurchla, Theresa L Murphy & Kenneth M Murphy

  2. Department of Experimental Medicine, University of Perugia, Via del Giochetto, Perugia, 06122, Italy

    Francesca Fallarino

  3. Department of Molecular Biology & Pharmacology, Washington University School of Medicine, Box 8103, 660 South Euclid Avenue, St. Louis, 63110, Missouri, USA

    Natalie Zimmerman, Julia Sim & John H Russell

  4. Department of Molecular and Cell Biology, Howard Hughes Medical Institute, Cancer Research Laboratory, University of California at Berkeley, Berkeley, 94720, California, USA

    Xingxing Zang & James P Allison

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Watanabe, N., Gavrieli, M., Sedy, J. et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol 4, 670–679 (2003). https://doi.org/10.1038/ni944

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