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Gene Review

BTLA  -  B and T lymphocyte associated

Homo sapiens

Synonyms: B-and T-lymphocyte attenuator, B-and T-lymphocyte-associated protein, BTLA1, CD272
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Disease relevance of BTLA


High impact information on BTLA

  • The new CD28 families members, ICOS, PD-1, and BTLA, are inducibly expressed on T cells, and they have important roles in regulating previously activated T cells [4].
  • PD-1 and BTLA also are expressed on B cells and may have broader immunoregulatory functions [4].
  • The interaction of BTLA, which belongs to the CD28 family of the immunoglobulin superfamily, and HVEM, a costimulatory tumor-necrosis factor (TNF) receptor (TNFR), is quite unique in that it is the only receptor-ligand interaction that directly bridges these two families of receptors [5].
  • Recently a new inhibitory immunoglobulin domain-containing lymphocyte receptor was identified on the basis of its T helper 1 (T(H)1)-selective expression in murine T cell lines, which was named B and T lymphocyte attenuator (BTLA) [5].
  • Finally, as studies of BTLA are just now beginning to extend beyond the initial characterizations, it is becoming clear that there are many complex issues remaining to be resolved, particularly potential polymorphisms that may engender disease susceptibility in the human [5].

Biological context of BTLA


Anatomical context of BTLA

  • Although cytotoxic T lymphocyte antigen 4 and programmed death-1 interact with B7-Ig family counter receptors, the ligand for BTLA is less clear [8].
  • The exception is BTLA (B and T lymphocyte attenuator), which instead interacts with the tumor necrosis factor receptor superfamily member HVEM (herpes virus entry mediator) [9].
  • Attenuating lymphocyte activity: the crystal structure of the BTLA-HVEM complex [9].
  • Polarized Th1 and Th2 cells contained both BTLA-positive and BTLA-negative populations, but the extended culture diminished BTLA expression [10].

Associations of BTLA with chemical compounds

  • This structure shows that BTLA binds the N-terminal cysteine-rich domain of HVEM and employs a unique binding surface compared with other CD28-like receptors [9].

Physical interactions of BTLA

  • We previously identified two tyrosine-containing signaling motifs in the cytoplasmic domain of BTLA that interact with the SHP-1 and SHP-2 phosphatases [11].

Regulatory relationships of BTLA

  • Cross-linking BTLA with an agonistic mAb inhibited T cell proliferation and the production of the cytokines IFN-gamma and IL-10 in response to anti-CD3 stimulation [10].

Other interactions of BTLA

  • Despite structural similarities to other CD28-like members, BTLA represents a unique co-receptor [9].
  • To better understand this interaction, we determined the 2.8-A crystal structure of the BTLA-HVEM complex [9].
  • Moreover, the structure shows that BTLA recognizes the same surface on HVEM as gD (herpes virus glycoprotein D) and utilizes a similar binding motif [9].
  • In addition, the expression of BTLA was increased in the CD4(+) and CD8(+) T cells of pleural fluid in lung cancer patients [12].
  • The three identified groups of inhibitory B7-recognizing receptors (CTLA-4, PD-1 and BTLA) are only expressed on activated hematopoietic cells, thus exclusively regulating ongoing immune responses in lymphoid organs and the periphery [13].

Analytical, diagnostic and therapeutic context of BTLA

  • BTLA-mediated inhibition of T cell activation occurred during both primary CD4+ T cell responses and secondary CD4+ and CD8+ T cell responses, suggesting that BTLA ligation sends a constitutive "off" signal to T cells and thus might play an important role in the maintenance of T cell tolerance [10].


  1. Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway. Cheung, T.C., Humphreys, I.R., Potter, K.G., Norris, P.S., Shumway, H.M., Tran, B.R., Patterson, G., Jean-Jacques, R., Yoon, M., Spear, P.G., Murphy, K.M., Lurain, N.S., Benedict, C.A., Ware, C.F. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. B and T lymphocyte attenuator-mediated signal transduction provides a potent inhibitory signal to primary human CD4 T cells that can be initiated by multiple phosphotyrosine motifs. Chemnitz, J.M., Lanfranco, A.R., Braunstein, I., Riley, J.L. J. Immunol. (2006) [Pubmed]
  3. BTLA, a new inhibitory B7 family receptor with a TNFR family ligand. Zeng, C., Wu, T., Zhen, Y., Xia, X.P., Zhao, Y. Cell. Mol. Immunol. (2005) [Pubmed]
  4. The B7 family revisited. Greenwald, R.J., Freeman, G.J., Sharpe, A.H. Annu. Rev. Immunol. (2005) [Pubmed]
  5. BTLA and HVEM Cross Talk Regulates Inhibition and Costimulation. Gavrieli, M., Sedy, J., Nelson, C.A., Murphy, K.M. Adv. Immunol. (2006) [Pubmed]
  6. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Sedy, J.R., Gavrieli, M., Potter, K.G., Hurchla, M.A., Lindsley, R.C., Hildner, K., Scheu, S., Pfeffer, K., Ware, C.F., Murphy, T.L., Murphy, K.M. Nat. Immunol. (2005) [Pubmed]
  7. Costimulatory receptors in jawed vertebrates: Conserved CD28, odd CTLA4 and multiple BTLAs. Bernard, D., Hansen, J.D., Du Pasquier, L., Lefranc, M.P., Benmansour, A., Boudinot, P. Dev. Comp. Immunol. (2007) [Pubmed]
  8. A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator. Gonzalez, L.C., Loyet, K.M., Calemine-Fenaux, J., Chauhan, V., Wranik, B., Ouyang, W., Eaton, D.L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  9. Attenuating lymphocyte activity: the crystal structure of the BTLA-HVEM complex. Compaan, D.M., Gonzalez, L.C., Tom, I., Loyet, K.M., Eaton, D., Hymowitz, S.G. J. Biol. Chem. (2005) [Pubmed]
  10. Expression and function of the B and T lymphocyte attenuator (BTLA/CD272) on human T cells. Otsuki, N., Kamimura, Y., Hashiguchi, M., Azuma, M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  11. Association of Grb-2 and PI3K p85 with phosphotyrosile peptides derived from BTLA. Gavrieli, M., Murphy, K.M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  12. Distinct expression and inhibitory function of B and T lymphocyte attenuator on human T cells. Wang, X.F., Chen, Y.J., Wang, Q., Ge, Y., Dai, Q., Yang, K.F., Zhou, Y.H., Hu, Y.M., Mao, Y.X., Zhang, X.G. Tissue Antigens (2007) [Pubmed]
  13. The regulation of lymphocyte activation by inhibitory receptors. Leibson, P.J. Curr. Opin. Immunol. (2004) [Pubmed]
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