B and T Lymphocyte Attenuator Exhibits Structural and Expression Polymorphisms and Is Highly Induced in Anergic CD4+ T Cells 1

B and T lymphocyte attenuator (BTLA) was initially identified as expressed on Th1 cells and B cells, but recently reported to be expressed by macrophages, dendritic cells, and NK cells as well. To address this discrepancy we generated a panel of BTLA-specific mAbs and characterized BTLA expression under various activation conditions. We report the existence of three distinct BTLA alleles among 23 murine strains, differing both in Ig domain structure and cellular distribution of expression on lymphoid subsets. The BALB/c and MRL/lpr alleles differ at one amino acid residue, but C57BL/6 has nine additional differences and alters the predicted cysteine bonding pattern. The BALB/c BTLA allele is also expressed by B cells, T cells, and dendritic cells, but not macrophages or NK cells. However, C57BL/6 BTLA is expressed on CD11b+ macrophages and NK cells. Finally, in CD4+ T cells, BTLA is expressed most highly following Ag-specific induction of anergy in vivo, and unlike programmed death-1 and CTLA-4, not expressed by CD25+ regulatory T cells. These results clarify discrepancies regarding BTLA expression, suggest that structural and expression polymorphisms be considered when analyzing BTLA in various murine backgrounds, and indicate a possible role in anergic CD4+ T cells.

[1]  C. Ware,et al.  B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator , 2005, Nature Immunology.

[2]  G. Freeman,et al.  PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J. Kaye,et al.  References Subscriptions Permissions Email Alerts An Inhibitory Ig Superfamily Protein Expressed by Lymphocytes and APCs Is Also an Early Marker of Thymocyte Positive Selection , 2013 .

[4]  Jeanne Kowalski,et al.  Non-parametric, hypothesis-based analysis of microarrays for comparison of several phenotypes , 2004, Bioinform..

[5]  K. Murphy,et al.  Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2. , 2003, Biochemical and biophysical research communications.

[6]  D. Fremont,et al.  Enhanced Immune Presentation of a Single-chain Major Histocompatibility Complex Class I Molecule Engineered to Optimize Linkage of a C-terminally Extended Peptide* , 2003, Journal of Biological Chemistry.

[7]  J. Allison,et al.  BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1 , 2003, Nature Immunology.

[8]  C. Drake,et al.  CD4+ T Cells Pass Through an Effector Phase During the Process of In Vivo Tolerance Induction , 2003, The Journal of Immunology.

[9]  D. Kranz,et al.  A yeast display system for engineering functional peptide-MHC complexes. , 2003, Journal of immunological methods.

[10]  T. Okazaki,et al.  New regulatory co-receptors: inducible co-stimulator and PD-1. , 2002, Current opinion in immunology.

[11]  Yoshimasa Tanaka,et al.  Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Michael S. Kuhns,et al.  CTLA-4: new insights into its biological function and use in tumor immunotherapy , 2002, Nature Immunology.

[13]  A. Adler,et al.  CD4 Cell Priming and Tolerization Are Differentially Programmed by APCs upon Initial Engagement1 , 2002, The Journal of Immunology.

[14]  G. Freeman,et al.  The B7–CD28 superfamily , 2002, Nature Reviews Immunology.

[15]  Jianfei Yang,et al.  T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells , 2002, Nature Immunology.

[16]  C. Thompson,et al.  T-cell regulation by CD28 and CTLA-4 , 2001, Nature Reviews Immunology.

[17]  G. Freeman,et al.  PD-L2 is a second ligand for PD-1 and inhibits T cell activation , 2001, Nature Immunology.

[18]  J. Gutiérrez-Ramos,et al.  The expanding B7 superfamily: Increasing complexity in costimulatory signals regulating T cell function , 2001, Nature Immunology.

[19]  J. Allison,et al.  ICOS co-stimulatory receptor is essential for T-cell activation and function , 2001, Nature.

[20]  T. Boone,et al.  Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS. , 2000, International immunology.

[21]  G. Stark,et al.  Selective loss of type I interferon-induced STAT4 activation caused by a minisatellite insertion in mouse Stat2 , 2000, Nature Immunology.

[22]  David W. Marsh,et al.  In Vivo CD4+ T Cell Tolerance Induction Versus Priming Is Independent of the Rate and Number of Cell Divisions1 , 2000, The Journal of Immunology.

[23]  G. Zhu,et al.  Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS. , 2000, Blood.

[24]  T. Mak,et al.  T-cell co-stimulation through B7RP-1 and ICOS , 1999, Nature.

[25]  W. Sha,et al.  B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFalpha. , 1999, Immunity.

[26]  Andreas Hutloff,et al.  ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28 , 1999, Nature.

[27]  Andreas Hutloff,et al.  ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28 , 1999, Nature.

[28]  David W. Marsh,et al.  CD4+ T Cell Tolerance to Parenchymal Self-Antigens Requires Presentation by Bone Marrow–derived Antigen-presenting Cells , 1998, The Journal of experimental medicine.

[29]  K D Wittrup,et al.  Isolation of anti-T cell receptor scFv mutants by yeast surface display. , 1997, Protein engineering.

[30]  T Pawson,et al.  Specific motifs recognized by the SH2 domains of Csk, 3BP2, fps/fes, GRB-2, HCP, SHC, Syk, and Vav , 1994, Molecular and cellular biology.

[31]  C. Hsieh,et al.  Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. , 1993, Science.

[32]  T. Honjo,et al.  Induced expression of PD‐1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. , 1992, The EMBO journal.