Alternative titles; symbols
HGNC Approved Gene Symbol: BTLA
Cytogenetic location: 3q13.2 Genomic coordinates (GRCh38) : 3:112,463,966-112,499,624 (from NCBI)
By microarray analysis and screening of mouse splenocyte and human T-cell cDNA libraries, Watanabe et al. (2003) obtained full-length cDNAs encoding BTLA. The predicted 289-amino acid protein contains a signal peptide, 3 potential N-linked glycosylation sites, a variable-type Ig domain, a transmembrane region, and a 100-residue intracellular domain with a GRB2 (108355)-interaction site and 2 immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Watanabe et al. (2003) also identified a BTLA splice variant lacking exon 2, which encodes the Ig domain. Northern blot analysis revealed expression in lymph node and spleen, as well as in polarized Th1 but not Th2 cells. Flow cytometric analysis demonstrated surface expression of a transmembrane protein. Immunoblot analysis showed expression of a glycosylated protein that could be phosphorylated on tyrosines in the ITIMs.
Watanabe et al. (2003) showed that BTLA could be induced to associate with SHP1 (176883) and SHP2 (176876). Functional analysis indicated that BTLA can modestly inhibit antigen-induced, but not chemically induced, production of IL2 (147680) by mouse hybridoma T cells. FACS analysis established that BTLA interacts with B7H4 (608162), a protein with a signal peptide and 2 Ig-like domains followed by a transmembrane region. Watanabe et al. (2003) proposed that BTLA is an inhibitory receptor on T lymphocytes that is similar to CTLA4 (123890) and PD1 (600244).
Sedy et al. (2005) obtained no evidence for direct interaction of BTLA with B7H4. Using tetramer analysis, they found that the extracellular Ig domain of BTLA interacted with the most membrane-distal cysteine-rich domain of HVEM (TNFRSF14; 602746). Flow cytometric and Western blot analyses showed that HVEM induced BTLA tyrosine phosphorylation and inhibited T-cell proliferation in a BTLA-dependent manner.
By surface plasmon resonance analysis of a secreted protein library, Gonzalez et al. (2005) identified HVEM as a specific, high-affinity coreceptor for BTLA. HVEM bound LIGHT (TNFSF14; 604520) at a site distinct from that bound by BTLA, and the 3 proteins could form a ternary complex. The BTLA-binding site in HVEM overlapped with that for herpes simplex virus glycoprotein D, indicating that BTLA likely interacts with the first cysteine-rich domain of HVEM. Binding of HVEM to BTLA inhibited T-cell proliferation. Gonzalez et al. (2005) concluded that HVEM and BTLA form an inhibitory coreceptor pair.
By genomic sequence analysis, Watanabe et al. (2003) determined that BTLA contains 5 exons and spans 33.1 kb.
Watanabe et al. (2003) generated Btla-deficient mice. Like Pd1 -/- and Ctla4 -/- T cells, proliferation in response to some mitogens was slightly enhanced in Btla -/- T cells, suggesting an inhibitory role for BTLA. Mice lacking Btla were also more susceptible to experimental autoimmune encephalomyelitis.
Steinberg et al. (2008) transferred naive Cd4 (186940)-positive/Cd45rb (151460)-high T cells, depleted of Cd25 (147730)-positive regulatory T cells, from Hvem -/- or wildtype mice into Rag (see 179615) -/- mice. They found that the naive wildtype T cells, and to a lesser extent the Hvem -/- T cells, induced progressive disease and colitis. However, in recipient mice that also lacked Hvem, there was a dramatic acceleration of intestinal inflammation, accompanied by increased T-cell cytokine production. Transfer of naive T cells into Hvem -/- Rag -/- recipients treated with anti-Btla reduced both cytokine production in vitro and colitis development in vivo. Steinberg et al. (2008) concluded that HVEM can act as a receptor to enhance immune responses by binding LIGHT and as a ligand to suppress immune responses by binding BTLA.
Gonzalez, L. C., Loyet, K. M., Calemine-Fenaux, J., Chauhan, V., Wranik, B., Ouyang, W., Eaton, D. L. A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator. Proc. Nat. Acad. Sci. 102: 1116-1121, 2005. [PubMed: 15647361] [Full Text: https://doi.org/10.1073/pnas.0409071102]
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. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nature Immun. 6: 90-98, 2005. [PubMed: 15568026] [Full Text: https://doi.org/10.1038/ni1144]
Steinberg, M. W., Turovskaya, O., Shaikh, R. B., Kim, G., McCole, D. F., Pfeffer, K., Murphy, K. M., Ware, C. F., Kronenberg, M. A crucial role for HVEM and BTLA in preventing intestinal inflammation. J. Exp. Med. 205: 1463-1476, 2008. [PubMed: 18519647] [Full Text: https://doi.org/10.1084/jem.20071160]
Watanabe, N., Gavrieli, M., Sedy, J. R., Yang, J., Fallarino, F., Loftin, S. K., Hurchla, M. A., Zimmerman, N., Sim, J., Zang, X., Murphy, T. L., Russell, J. H., Allison, J. P., Murphy, K. M. BTLA4 is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nature Immun. 4: 670-679, 2003. [PubMed: 12796776] [Full Text: https://doi.org/10.1038/ni944]