Attenuating Lymphocyte Activity

Five CD28-like proteins exert positive or negative effects on immune cells. Only four of these five receptors interact with members of the B7 family. 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). To better understand this interaction, we determined the 2. 8-Å crystal structure of the BTLA-HVEM complex. 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. Moreover, the structure shows that BTLA recognizes the same surface on HVEM as gD (herpes virus glycoprotein D) and utilizes a similar binding motif. Light scattering analysis demonstrates that the extracellular domain of BTLA is monomeric and that BTLA and HVEM form a 1: 1 complex. Alanine-scanning mutagenesis of HVEM was used to further define critical binding residues. Finally, BTLA adopts an immunoglobulin I-set fold. Despite structural similarities to other CD28-like members, BTLA represents a unique co-receptor. Five CD28-like proteins exert positive or negative effects on immune cells. Only four of these five receptors interact with members of the B7 family. 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). To better understand this interaction, we determined the 2. 8-Å crystal structure of the BTLA-HVEM complex. 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. Moreover, the structure shows that BTLA recognizes the same surface on HVEM as gD (herpes virus glycoprotein D) and utilizes a similar binding motif. Light scattering analysis demonstrates that the extracellular domain of BTLA is monomeric and that BTLA and HVEM form a 1: 1 complex. Alanine-scanning mutagenesis of HVEM was used to further define critical binding residues. Finally, BTLA adopts an immunoglobulin I-set fold. Despite structural similarities to other CD28-like members, BTLA represents a unique co-receptor. Co-receptor signaling is an important mechanism of coordinating and tightly regulating immune response. For instance, activation of naïve T cells requires a second co-stimulatory signal in addition to stimulation of the T cell receptor by engagement with peptide-MHC complexes. Conversely, co-inhibitory signals are required to maintain T cell self-tolerance and prevent autoimmunity (1Sharpe A. H. Freeman G. J. Nat. Rev. 2002; 2: 116-126Crossref Scopus (1406) Google Scholar). The CD28-like family is one important class of co-receptors. These members of the immunoglobulin superfamily (IgSF) 2The abbreviations used are: IgSFimmunoglobulin superfamilyBTLAB and T lymphocyte attenuatorCRDcysteine-rich domainCTLA4cytotoxic T lymphocyte antigen 4ECDextracellular domaingDherpesvirus glycoprotein DHVEMherpesvirus entry mediatorLIGHThomologous to lymphotoxin, showing inducible expression, and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytesTNFSFtumor necrosis factor superfamilyTNFRSFtumor necrosis factor receptor superfamilyLTαlymphotoxin αNi-NTAnickel-nitriloacetic acidHPLChigh performance liquid chromatography function as either co-stimulators (CD28 and inducible T cell costimulator) or co-inhibitors (CTLA-4, programmed death-1, and BTLA) in modulating immune cell activity (2Greenwald R. J. Freeman G. J. Sharpe A. H. Annu. Rev. Immunol. 2005; 23: 515-548Crossref PubMed Scopus (1963) Google Scholar). In general, these co-receptors are activated by members of the Ig containing B7 family (1Sharpe A. H. Freeman G. J. Nat. Rev. 2002; 2: 116-126Crossref Scopus (1406) Google Scholar). In addition to the CD28- and B7-like families of receptors and ligands, members of the TNF superfamilies of ligands and receptors (the TNFSF and TNFRSF respectively), such as OX40L-OX40, LIGHT-HVEM, CD27L-CD27, CD30L-CD30, and 4₁BBL-4₁BB, have also been reported to function as co-stimulators (3Watts T. H. Annu. Rev. Immunol. 2005; 23: 23-68Crossref PubMed Scopus (1131) Google Scholar). immunoglobulin superfamily B and T lymphocyte attenuator cysteine-rich domain cytotoxic T lymphocyte antigen 4 extracellular domain herpesvirus glycoprotein D herpesvirus entry mediator homologous to lymphotoxin, showing inducible expression, and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes tumor necrosis factor superfamily tumor necrosis factor receptor superfamily lymphotoxin α nickel-nitriloacetic acid high performance liquid chromatography Recently the CD28 family member BTLA was unexpectedly shown to bind and be activated by the TNFRSF member herpes virus entry mediator (HVEM, also known as TNFRSF14, HveA, ATAR, TR2, or LIGHTR) (4Gonzalez 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; 102: 1116-1121Crossref PubMed Scopus (212) Google Scholar, 5Sedy 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; 6: 90-98Crossref PubMed Scopus (499) Google Scholar). This is the first example of cross-talk between the CD28 family and the TNFRSF. Whereas HVEM has been previously described as a co-stimulator triggered by the TNF-like ligands lymphotoxin α (LTα) and LIGHT (6Granger S. W. Rickert S. Cytokine Growth Factor Rev. 2003; 14: 289-296Crossref PubMed Scopus (106) Google Scholar), recent results from HVEM knock-out mice as well as the interaction between BTLA and HVEM are consistent with HVEM playing a co-inhibitory role (7Wang Y. Subudhi S. K. Anders R. A. Lo J. Sun Y. Blink S. Wang J. Liu X. Mink K. Degrandi D. Pfeffer K. Fu Y. X. J. Clin. Investig. 2005; 115: 711-717Crossref PubMed Scopus (155) Google Scholar). In addition to binding BTLA, LIGHT, and LTα, human HVEM is also a host cell receptor for herpes simplex virus 1 by binding to herpes simplex virus 1 glycoprotein D (gD) (8Montgomery R. I. Warner M. S. Lum B. J. Spear P. G. Cell. 1996; 87: 427-436Abstract Full Text Full Text PDF PubMed Scopus (1007) Google Scholar). Structurally, the connection between the IgSF family represented by BTLA and the TNFRSF proteins such as HVEM is unexpected. Crystal structures of CD28, CTLA-4, and programmed death-1 have revealed that these co-stimulatory and co-inhibitor receptors are all members of the immunoglobulin superfamily with each protein containing an extracellular IgV domain (9Evans E. J. Esnouf R. M. Manso-Sancho R. Gilbert R. J. James J. R. Yu C. Fennelly J. A. Vowles C. Hanke T. Walse B. Hunig T. Sorensen P. Stuart D. I. Davis S. J. Nat. Immunol. 2005; 6: 271-279Crossref PubMed Scopus (127) Google Scholar, 10Metzler W. J. Bajorath J. Fenderson W. Shaw S. Y. Constantine K. L. Naemura J. Leytze G. Peach R. J. Lavoie T. B. Mueller L. Linsley P. S. Nat. Struct. Biol. 1997; 4: 527-531Crossref PubMed Scopus (112) Google Scholar, 11Zhang X. Schwartz J. C. Guo X. Bhatia S. Cao E. Lorenz M. Cammer M. Chen L. Zhang Z. Y. Edidin M. A. Nathenson S. G. Almo S. C. Immunity. 2004; 20: 337-347Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar). Based on sequence analysis, BTLA was also expected to contain an extracellular IgV domain. Similarly, the extracellular domains of B7-like proteins are comprised of Ig domains. Co-crystal structures of B7-1 and B7-2 bound to CTLA4 show that Ig domains from the receptor and ligand pack against each other forming a compact interface (12Schwartz J. C. Zhang X. Fedorov A. A. Nathenson S. G. Almo S. C. Nature. 2001; 410: 604-608Crossref PubMed Scopus (276) Google Scholar, 13Stamper C. C. Zhang Y. Tobin J. F. Erbe D. V. Ikemizu S. Davis S. J. Stahl M. L. Seehra J. Somers W. S. Mosyak L. Nature. 2001; 410: 608-611Crossref PubMed Scopus (373) Google Scholar). In contrast, the TNFSF and TNFRSF members are formed by very different structural elements and interact in a distinctive manner determined by the quaternary structure of TNF-like ligands. These proteins are homotrimeric or occasionally heterotrimeric proteins comprised of jelly-roll monomers. Multidomain TNFRSF family members are comprised of multiple pseudo-repeats of a cysteinerich motif. Structures of signaling complexes formed by TNF-like ligands and receptors show that the elongated receptors bind at monomer-monomer interfaces on the ligands in a manner much different from the compact B7-CD28-type interaction (14Bodmer J. L. Schneider P. Tschopp J. Trends Biochem. Sci. 2002; 27: Full Text Full Text PDF PubMed Scopus Google Scholar). The BTLA-HVEM interaction is also in that represents the first example of a TNFRSF as a and is one of a of of a TNFRSF with a In addition to the BTLA-HVEM and other which bind ligands, the receptor which binds the factor and which as a for the virus C. Sci. 2001; PubMed Scopus Google Scholar, M. T. Y. Y. B. J. 2004; PubMed Scopus Google Scholar). Crystal structures of the complexes show that gD protein interacts with the N-terminal cysteine-rich domain of HVEM on the surface the TNFSF binding A. J. C. C. R. J. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Similarly, the same surface on and a of to bind 2004; PubMed Scopus Google Scholar). that BTLA also binds to HVEM on the to the TNFSF binding (4Gonzalez 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; 102: 1116-1121Crossref PubMed Scopus (212) Google Scholar, 5Sedy 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; 6: 90-98Crossref PubMed Scopus (499) Google Scholar). To a of the interaction between the CD28-like protein BTLA and the TNFRSF member we have determined the 2. 8-Å crystal structure of the BTLA-HVEM complex. This structure shows that structural between BTLA and bind to an on HVEM a similar binding motif. have used mutagenesis and to critical on that binding in with the crystal Light scattering demonstrates that the extracellular domain of BTLA is monomeric and that BTLA and HVEM form a 1: 1 in Despite the and similarities between BTLA and the CD28 BTLA unique Moreover, compared with the binding BTLA a surface to interact with Finally, the BTLA-HVEM we a for a complex. and human BTLA (the is with the addition of a was expressed in from BTLA E. and the protein was on a as described D. M. W. J. C. S. R. A. P. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). and to with containing 1 1 and 1 The was at and the to with The was an with acid in and with a of to in acid at for a of and the was by by a of The was a with containing BTLA activity was protein was expressed in cells as previously described (4Gonzalez 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; 102: 1116-1121Crossref PubMed Scopus (212) Google Scholar). The a between the BTLA extracellular domain and the BTLA was from the domain by the addition of a of to in at the was with a and a protein BTLA was from the a human HVEM as in 1 is the first in the to the of HVEM in the and the N-terminal of was the and the was by and of in cells. virus was used to and protein was expressed for and the as described S. G. J. L. P. M. W. J. G. M. A. J. 2001; 20: PubMed Scopus Google to a and with was of to the N-terminal and the was at 4 against The was and an in of HVEM and of of cells. a a of human HVEM to as with a was also expressed and This the same HVEM as that used by A. J. C. C. R. J. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google and J. C. C. R. M. T. R. I. Warner M. S. Spear P. G. R. J. J. 1997; PubMed Google Scholar). For the BTLA-HVEM was by HVEM to E. BTLA and at for 1 The was and from HVEM with an in containing and to LIGHT extracellular domain was expressed and in the same manner as HVEM with a on in 1 of of cells. and of the BTLA-HVEM by at the formed in containing protein with an of containing The used to The to a containing with in liquid The to and the of the BTLA-HVEM complex. to 2. 8-Å was from a crystal at of the for at the Light The the W. 1997; Scopus Google Scholar). Structures of HVEM B in and BTLA structure determined and by D. and in used as to the structure of the BTLA-HVEM by which between and human BTLA, to The L. C. R. J. D Biol. 2004; PubMed Scopus Google a and K. P. D Biol. PubMed Scopus Google revealed for the The was with 2003; PubMed Scopus Google with on of BTLA and of The of BTLA in the as of the of the in crystal was for a with the of of A. This was as a and is an of of BTLA by and are shown in The for the BTLA-HVEM have been in the and and in to the cell is the of of a unique in to the in to the in to the BTLA-HVEM is as for of the which have been from of in the and of a in to the is the of of a unique is as for of the which have been from of in the and of a in a and mutagenesis was used as by the to in HVEM by was by the and LIGHT by the binding as previously described (4Gonzalez 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; 102: 1116-1121Crossref PubMed Scopus (212) Google with BTLA and of LIGHT binding was with LIGHT with or of LIGHT binding to was as a of cells with either or HVEM as previously described (4Gonzalez 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; 102: 1116-1121Crossref PubMed Scopus (212) Google cells as a negative of and HVEM was by as previously described HVEM in to an The HVEM is in all HVEM of are to that of HVEM as by the of cells a determined by Light was a in with a an was used for scattering and a or a with was used with a of 1 the scattering and the as the of was for the of the the signal from monomeric the The of the scattering was at and the of the was at The and all at BTLA in the used for and was at The structure of the human BTLA-HVEM was by the structures of the HVEM and the structure of BTLA as with the L. C. R. J. D Biol. 2004; PubMed Scopus Google Scholar). was with of the BTLA-HVEM forming the The structure was and to an of and The of BTLA and HVEM and In of BTLA, an from the well in the and are in the used the and the of the BTLA-HVEM are very This structure that human BTLA, BTLA is a compact domain of which are formed by and D in one and and in the other The are by and The the and the the N-terminal to the and the the B and This is in the of BTLA and is of the The and the are in IgSF domains. 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Moreover, as HVEM an to the is also that the BTLA-HVEM interaction between proteins on the same in different BTLA have been from mice These have been and to the from which M. A. J. R. Gavrieli M. Murphy T. L. Murphy K. M. J. Immunol. 2005; PubMed Scopus Google Scholar). The crystal structure of BTLA is of the The and at one the from the other by or in the extracellular Ig domain M. A. J. R. Gavrieli M. Murphy T. L. Murphy K. M. J. Immunol. 2005; PubMed Scopus Google Scholar). The structural and of these be on the structure of the human BTLA-HVEM complex. The is the between and at to the human human BTLA in In the the of a at this that a to the in be The containing be as to or between the is that in the a and an at and in of a with a of the and in the of the expected receptor binding are to to The in BTLA the HVEM binding and are expected to either BTLA structure or HVEM In of the of of the are to be in with all are expected to for proteins with for of the BTLA-HVEM mutagenesis T. J. 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BTLA to be monomeric in This in with the of between the in the that the interaction between the is of the gD and BTLA on gD of the BTLA-HVEM structure to the previously determined structure A. J. C. C. R. J. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google shows that the BTLA and gD binding on HVEM are and similar structural as well as similar In the BTLA binding on HVEM is the gD binding of the HVEM that surface binding with BTLA, are also in binding BTLA, gD a that an interaction with HVEM between gD and HVEM are formed by a in gD the surface of HVEM at the of and The interaction between the by BTLA or gD and HVEM are very similar and are at the of the BTLA-HVEM and Despite the of the structure and function of this in BTLA and a of the of the shows that have sequence and sequence the of the in forming the the similar in BTLA and in gD the of these pack against in which was by mutagenesis as important for BTLA binding and is important for gD binding as well A. R. J. J. 2002; PubMed Scopus Google Scholar). The of these binding are also the structural of the BTLA binding by A. R. J. J. 2002; PubMed Scopus Google Scholar, A. R. J. J. 2003; PubMed Scopus Google used to the binding and in HVEM for which in gD of these also in this and we that at four of and also BTLA The gD also and which are for BTLA to be the of the gD and BTLA binding as of this by BTLA and gD Whereas gD and BTLA bind HVEM and for the same on structures are different gD is formed by a Ig domain that is with a N-terminal structure and a The gD Ig domain HVEM the N-terminal of the to HVEM and is by an from the A. J. C. C. R. J. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In contrast, BTLA of an Ig domain and this domain to bind Despite these BTLA and gD have on a very similar structural and for binding This that of this is a the HVEM at the of the BTLA and gD binding is one of the elements of structure in the This is in S. G. G. M. M. A. Cell. 4: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Chen Stuart D. I. Nat. Struct. Biol. 6: PubMed Scopus Google and A. W. R. C. W. Cell. Full Text PDF PubMed Scopus Google Scholar), the other TNFRSF family members that have been In the is in The structure of which has a a at this is by the the sequence is at this in of TNFRSF members and is is and is is in of TNFRSF This of sequence and structure that other TNFRSF interact with binding by forming a similar binding motif. BTLA a of the I-set of IgSF to on sequence analysis Gavrieli M. J. R. J. S. K. Hurchla M. A. J. X. Murphy T. L. Murphy K. M. Nat. Immunol. 2003; 4: PubMed Scopus Google Scholar), of the BTLA structure that to a different of the IgSF the CD28-like family. IgSF domains be 4 the 1 and on structures and Y. C. J. Biol. PubMed Scopus Google Scholar). of the of I-set domains is the of a The structure shows that the BTLA domain this and is better described as a member of the I-set of Ig domains. of which I-set and Ig domains from other Ig domains Y. C. J. Biol. PubMed Scopus Google Scholar), this analysis The structures of CTLA4 W. J. Bajorath J. Fenderson W. Shaw S. Y. Constantine K. L. Naemura J. Leytze G. Peach R. J. Lavoie T. B. Mueller L. Linsley P. S. Nat. Struct. Biol. 1997; 4: 527-531Crossref PubMed Scopus (112) Google Scholar), programmed death-1 X. Schwartz J. C. Guo X. Bhatia S. Cao E. Lorenz M. Cammer M. Chen L. Zhang Z. Y. Edidin M. A. Nathenson S. G. Almo S. C. Immunity. 2004; 20: 337-347Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar), and CD28 (9Evans E. J. Esnouf R. M. Manso-Sancho R. Gilbert R. J. James J. R. Yu C. Fennelly J. A. Vowles C. Hanke T. Walse B. Hunig T. Sorensen P. Stuart D. I. Davis S. J. Nat. Immunol. 2005; 6: 271-279Crossref PubMed Scopus (127) Google as well as the sequence of inducible T cell that these proteins all a and are better described as members of the of Ig domains. these four known CD28-like proteins are all in on BTLA is on This analysis, as well as the that BTLA binds a different that BTLA is from the CD28 family. BTLA a with CD28 structures of CTLA4 bound to B7-1 and which is expected to be of CD28 family shows that the sequence in the CTLA4 in with on the and form a binding surface (12Schwartz J. C. Zhang X. Fedorov A. A. Nathenson S. G. Almo S. C. Nature. 2001; 410: 604-608Crossref PubMed Scopus (276) Google Scholar, 13Stamper C. C. Zhang Y. Tobin J. F. Erbe D. V. Ikemizu S. Davis S. J. Stahl M. L. Seehra J. Somers W. S. Mosyak L. Nature. 2001; 410: 608-611Crossref PubMed Scopus (373) Google Scholar). In contrast, the BTLA binding surface is the of the I-set Ig domain to the CTLA4 binding surface the complexes that at of these proteins are of forming a at the For instance, a CTLA4 interact with B7-like This of interaction to the of a of CTLA4 in high of or domains (12Schwartz J. C. Zhang X. Fedorov A. A. Nathenson S. G. Almo S. C. Nature. 2001; 410: 604-608Crossref PubMed Scopus (276) Google Scholar, 13Stamper C. C. Zhang Y. Tobin J. F. Erbe D. V. Ikemizu S. Davis S. J. Stahl M. L. Seehra J. Somers W. S. Mosyak L. Nature. 2001; 410: 608-611Crossref PubMed Scopus (373) Google Scholar). In contrast, scattering on BTLA-HVEM extracellular domain complexes that the in at high is a BTLA-HVEM BTLA signaling be activated in a different manner that of CTLA4 or or at the BTLA of T cell for and HVEM addition to binding BTLA, HVEM is also known to bind TNFSF family members LIGHT and BTLA binding the TNFSF binding on the of HVEM and HVEM be to bind BTLA and either LIGHT or to form a complex. have been to a containing LIGHT, and BTLA by chromatography the of this has been M. and S. G. LIGHT is required for BTLA the of a is at this (7Wang Y. Subudhi S. K. Anders R. A. Lo J. Sun Y. Blink S. Wang J. Liu X. Mink K. Degrandi D. Pfeffer K. Fu Y. X. J. Clin. Investig. 2005; 115: 711-717Crossref PubMed Scopus (155) Google Scholar, Gavrieli M. J. R. J. S. K. Hurchla M. A. J. X. Murphy T. L. Murphy K. M. Nat. Immunol. 2003; 4: PubMed Scopus Google Scholar). of a was by that the be very similar in to the A. W. R. C. W. Cell. Full Text PDF PubMed Scopus Google Scholar). The of this that LIGHT and BTLA be expressed on the same HVEM be expressed on a different cell Finally, BTLA of is to have the same on HVEM activation as LIGHT which of HVEM to and signal BTLA-HVEM of and and demonstrates the of that very different BTLA and have on the same binding also similar elements of structure to bind In the BTLA-HVEM structure further BTLA from the CD28 family of BTLA and CTLA4 in structure and binding been expected from acid BTLA have from the CD28-like family and to the TNF receptor HVEM as an and this was Potter K. G. P. S. G. R. M. Spear P. G. Murphy K. M. Ware C. F. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: PubMed Scopus Google a mutagenesis on the that the in HVEM BTLA binding and that the BTLA binding is HVEM and is from the gD binding This is with the crystal structure and mutagenesis results reported for BTLA, R. for BTLA, and M. for the scattering R. for M. and the at for with C. for on IgSF for on the and in and protein