Key Points
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Herpesvirus-entry mediator (HVEM) is a co-stimulatory member of the tumour-necrosis factor (TNF) family of receptors that are expressed by T cells. It interacts with TNF family members LIGHT and lymphotoxin-α (LTα). It has also recently been shown to have an unusual interaction with B- and T-lymphocyte attenuator (BTLA), an inhibitory molecule expressed by T cells, such as cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death 1 (PD1).
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Trimeric LIGHT or LTα proteins are likely to induce trimerization of HVEM receptors. By contrast, structural studies have shown that BTLA interacts with a different surface of the HVEM molecule compared with LIGHT, inducing a dimer, and leading to the possibility of a ternary complex containing HVEM, LIGHT and BTLA.
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HVEM, LIGHT, and BTLA are all widely expressed on T cells and antigen presenting cells. The expression of each of these receptors is dynamically regulated: HVEM expression generally decreases with activation, whereas LIGHT and BTLA expression generally increases with activation.
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BTLA, like CTLA4 and PD1, recruits Src homology 2 (SH2)-domain-containing protein tyrosine phosphatases (SHPs) to its cytoplasmic domain following HVEM ligation. These phosphatases have been shown to block T-cell-receptor signal transduction after CTLA4 or PD1 ligation.
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HVEM co-stimulates T-cell activation following ligation with LIGHT. HVEM has co-stimulatory effects on many other cells including B cells, dendritic cells, natural killer cells, monocytes and neutrophils that result in increases in proliferation and activation.
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Mice deficient in LIGHT show clear defects in T-cell activation. Mice deficient in HVEM and BTLA, however, both show defects in T-cell inhibition, further indicating the linkage of these two proteins in vivo.
Abstract
The interaction between B- and T-lymphocyte attenuator (BTLA), an inhibitory receptor whose extracellular domain belongs to the immunoglobulin superfamily, and herpesvirus-entry mediator (HVEM), a co-stimulatory tumour-necrosis factor receptor, is unique in that it is the only receptor–ligand interaction that directly bridges these two families of receptors. This interaction has raised many questions about how receptors from two different families could interact and what downstream signalling events might occur as a result of receptor ligation. As we discuss, recent studies show that engagement of HVEM with its endogenous ligand (LIGHT) from the tumour-necrosis factor family induces a powerful immune response, whereas HVEM interactions with BTLA negatively regulate T-cell responses.
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References
Sharpe, A. H. & Freeman, G. J. The B7-CD28 superfamily. Nature Rev. Immunol. 2, 116–126 (2002).
Greenwald, R. J., Freeman, G. J. & Sharpe, A. H. The B7 family revisited. Annu. Rev. Immunol. 23, 515–548 (2005).
Croft, M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nature Rev. Immunol. 3, 609–620 (2003).
Watts, T. H. TNF/TNFR family members in costimulation of T cell responses. Annu. Rev. Immunol. 23, 23–68 (2005).
Chen, L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nature Rev. Immunol. 4, 336–347 (2004).
Montgomery, R. I. et al. Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 87, 427–436 (1996).
Hsu, H. et al. ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5. J. Biol. Chem. 272, 13471–13474 (1997).
Marsters, S. A. et al. Herpesvirus entry mediator, a member of the tumor necrosis factor receptor (TNFR) family, interacts with members of the TNFR-associated factor family and activates the transcription factors NF-κB and AP-1. J. Biol. Chem. 272, 14029–14032 (1997).
Kwon, B. S. et al. A newly identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation. J. Biol. Chem. 272, 14272–14276 (1997).
Mauri, D. N. et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin α are ligands for herpesvirus entry mediator. Immunity 8, 21–30 (1998).
Smith, C. A., Farrah, T. & Goodwin, R. G. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell 76, 959–962 (1994).
Rooney, I. A. et al. The lymphotoxin-β receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. J. Biol. Chem. 275, 14307–14315 (2000).
Yu, K. Y. et al. A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J. Biol. Chem. 274, 13733–13736 (1999).
Banner, D. W. et al. Crystal structure of the soluble human 55 kD TNF receptor-human TNF β complex: implications for TNF receptor activation. Cell 73, 431–445 (1993).
Bodmer, J. L., Schneider, P. & Tschopp, J. The molecular architecture of the TNF superfamily. Trends Biochem. Sci. 27, 19–26 (2002).
Sarrias, M. R. et al. The three HveA receptor ligands, gD, LT-α and LIGHT bind to distinct sites on HveA. Mol. Immunol. 37, 665–673 (2000).
Whitbeck, J. C. et al. Localization of the gD-binding region of the human herpes simplex virus receptor, HveA. J. Virol. 75, 171–180 (2001).
Carfi, A. et al. Herpes simplex virus glycoprotein D bound to the human receptor HveA. Mol. Cell 8, 169–179 (2001).
Watanabe, N. et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nature Immunol. 4, 670–679 (2003).
Han, P. et al. An inhibitory Ig superfamily protein expressed by lymphocytes and APCs is also an early marker of thymocyte positive selection. J. Immunol. 172, 5931–5939 (2004). References 19 and 20 describe the identification of BTLA and show SHP2 recruitment to its cytoplasmic region. These studies also show that BTLA-deficient T cells are hyperactive in response to a TCR stimulus.
Sedy, J. R. et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nature Immunol. 6, 90–98 (2005).
Gonzalez, L. C. et al. A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator. Proc. Natl Acad. Sci. USA 102, 1116–1121 (2005). References 21 and 22 identify HVEM as the ligand for BTLA using screens of a transcript expression library, and of a secreted protein library, respectively. Both papers also show that HVEM ligation of BTLA inhibits T-cell proliferation.
Cheung, T. C. et al. Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway. Proc. Natl Acad. Sci. USA 102, 13218–13223 (2005).
Compaan, D. M. et al. Attenuating lymphocyte activity: the crystal structure of the BTLA–HVEM complex. J. Biol. Chem. 280, 39553–39561 (2005). Shows the co-crystal of BTLA and HVEM, with BTLA interacting with CRD1 and CRD2 of HVEM. The authors propose that HVEM, BTLA and LIGHT could interact in a ternary complex, as the binding of BTLA and LIGHT to HVEM is not exclusive.
Hurchla, M. A. et al. B and T lymphocyte attenuator exhibits structural and expression polymorphisms and is highly induced in anergic CD4+ T cells. J. Immunol. 174, 3377–3385 (2005).
Loyet, K. M. et al. Proteomic profiling of surface proteins on Th1 and Th2 cells. J. Proteome Res. 4, 400–409 (2005).
Otsuki, N. et al. Expression and function of the B and T lymphocyte attenuator (BTLA/CD272) on human T cells. Biochem. Biophys. Res. Commun. 344, 1121–1127 (2006).
Morel, Y. et al. Reciprocal expression of the TNF family receptor herpes virus entry mediator and its ligand LIGHT on activated T cells: LIGHT down-regulates its own receptor. J. Immunol. 165, 4397–4404 (2000).
Morel, Y. et al. The TNF superfamily members LIGHT and CD154 (CD40 ligand) costimulate induction of dendritic cell maturation and elicit specific CTL activity. J. Immunol. 167, 2479–2486 (2001).
Shi, G. et al. Mouse T cells receive costimulatory signals from LIGHT, a TNF family member. Blood 100, 3279–3286 (2002).
Tamada, K. et al. LIGHT, a TNF-like molecule, costimulates T cell proliferation and is required for dendritic cell-mediated allogeneic T cell response. J. Immunol. 164, 4105–4110 (2000).
Duhen, T. et al. LIGHT costimulates CD40 triggering and induces immunoglobulin secretion; a novel key partner in T cell-dependent B cell terminal differentiation. Eur. J. Immunol. 34, 3534–3541 (2004).
Harrop, J. A. et al. Antibodies to TR2 (herpesvirus entry mediator), a new member of the TNF receptor superfamily, block T cell proliferation, expression of activation markers, and production of cytokines. J. Immunol. 161, 1786–1794 (1998).
Wang, Y. et al. The role of herpesvirus entry mediator as a negative regulator of T cell-mediated responses. J. Clin. Invest. 115, 711–717 (2005). The first description of HVEM-deficient mice. T cells from these mice show increased activation in response to ConA stimulation, compared with LIGHT-deficient T cells, and the mice are much more sensitive to ConA-induced liver disease than wild-type mice.
Shaikh, R. B. et al. Constitutive expression of LIGHT on T cells leads to lymphocyte activation, inflammation, and tissue destruction. J. Immunol. 167, 6330–6337 (2001).
Teft, W. A., Kirchhof, M. G. & Madrenas, J. A molecular perspective of CTLA-4 function. Annu. Rev. Immunol. 24, 65–97 (2006).
Schwartz, J. C. et al. Structural basis for co-stimulation by the human CTLA-4/B7–2 complex. Nature 410, 604–608 (2001).
Stamper, C. C. et al. Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature 410, 608–611 (2001).
Shiratori, T. et al. Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2. Immunity 6, 583–589 (1997).
Miyatake, S. et al. Src family tyrosine kinases associate with and phosphorylate CTLA-4 (CD152). Biochem. Biophys. Res. Commun. 249, 444–448 (1998).
Chuang, E. et al. Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases. J. Immunol. 162, 1270–1277 (1999).
Marengere, L. E. et al. Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 272, 1170–1173 (1996).
Lee, K. M. et al. Molecular basis of T cell inactivation by CTLA-4. Science 282, 2263–2266 (1998).
Guntermann, C. & Alexander, D. R. CTLA-4 suppresses proximal TCR signaling in resting human CD4+ T cells by inhibiting ZAP-70 Tyr319 phosphorylation: a potential role for tyrosine phosphatases. J. Immunol. 168, 4420–4429 (2002).
Schneider, H. & Rudd, C. E. Tyrosine phosphatase SHP-2 binding to CTLA-4: absence of direct YVKM/YFIP motif recognition. Biochem. Biophys. Res. Commun. 269, 279–283 (2000).
Schneider, H. et al. A regulatory role for cytoplasmic YVKM motif in CTLA-4 inhibition of TCR signaling. Eur. J. Immunol. 31, 2042–2050 (2001).
Nakaseko, C. et al. Cytotoxic T lymphocyte antigen 4 (CTLA-4) engagement delivers an inhibitory signal through the membrane-proximal region in the absence of the tyrosine motif in the cytoplasmic tail. J. Exp. Med. 190, 765–774 (1999).
Chuang, E. et al. The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity 13, 313–322 (2000).
Baroja, M. L. et al. Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A. J. Immunol. 168, 5070–5078 (2002).
Alegre, M. L., Frauwirth, K. A. & Thompson, C. B. T-cell regulation by CD28 and CTLA-4. Nature Rev. Immunol. 1, 220–228 (2001).
Frauwirth, K. A. & Thompson, C. B. Regulation of T lymphocyte metabolism. J. Immunol. 172, 4661–4665 (2004).
Boudreau, R. T. & Hoskin, D. W. The use of okadaic acid to elucidate the intracellular role(s) of protein phosphatase 2A: lessons from the mast cell model system. Int. Immunopharmacol. 5, 1507–1518 (2005).
Zhang, Y. & Allison, J. P. Interaction of CTLA-4 with AP50, a clathrin-coated pit adaptor protein. Proc. Natl Acad. Sci. USA 94, 9273–9278 (1997).
Bradshaw, J. D. et al. Interaction of the cytoplasmic tail of CTLA-4 (CD152) with a clathrin-associated protein is negatively regulated by tyrosine phosphorylation. Biochemistry 36, 15975–15982 (1997).
Yi, L. A., Hajialiasgar, S. & Chuang, E. Tyrosine-mediated inhibitory signals contribute to CTLA-4 function in vivo. Int. Immunol. 16, 539–547 (2004).
Zhang, X. et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity 20, 337–347 (2004).
Okazaki, T. et al. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting Src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc. Natl Acad. Sci. USA 98, 13866–13871 (2001).
Latchman, Y. et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nature Immunol. 2, 261–268 (2001).
Chemnitz, J. M. et al. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173, 945–954 (2004).
Sheppard, K. A. et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3z signalosome and downstream signaling to PKCq. FEBS Lett. 574, 37–41 (2004).
Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25, 9543–9553 (2005).
Gavrieli, M. & Murphy, K. M. Association of Grb-2 and PI3K p85 with phosphotyrosile peptides derived from BTLA. Biochem. Biophys. Res. Commun. 345, 1440–1445 (2006).
Gavrieli, M. 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. Biochem. Biophys. Res. Commun. 312, 1236–1243 (2003).
Krieg, C. et al. Functional analysis of B and T lymphocyte attenuator engagement on CD4+ and CD8+ T cells. J. Immunol. 175, 6420–6427 (2005).
Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2005).
Harrop, J. A. et al. Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth. J. Biol. Chem. 273, 27548–27556 (1998).
Granger, S. W. & Rickert, S. LIGHT–HVEM signaling and the regulation of T cell-mediated immunity. Cytokine Growth Factor Rev. 14, 289–296 (2003).
Force, W. R. et al. Mouse lymphotoxin-β receptor. Molecular genetics, ligand binding, and expression. J. Immunol. 155, 5280–5288 (1995).
Murphy, M. et al. Expression of the lymphotoxin β receptor on follicular stromal cells in human lymphoid tissues. Cell Death Differ. 5, 497–505 (1998).
Wan, X. et al. A TNF family member LIGHT transduces costimulatory signals into human T cells. J. Immunol. 169, 6813–6821 (2002).
Tamada, K. et al. Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. Nature Med. 6, 283–289 (2000). Together with references 31 and 66, this paper shows that LIGHT co-stimulates T-cell proliferation and effector function, including cytokine production and cytolysis.
Yu, P. et al. Priming of naive T cells inside tumors leads to eradication of established tumors. Nature Immunol. 5, 141–149 (2004). Highlights the dual activities of LIGHT in the induction of inflammation and co-stimulation of T-cell activation. Both of these effects cooperate in this system to induce potent immune responses, resulting in clearance of established allogenic tumours.
Wu, Q. et al. The requirement of membrane lymphotoxin for the presence of dendritic cells in lymphoid tissues. J. Exp. Med. 190, 629–638 (1999).
Wang, Y. G. et al. Stimulating lymphotoxin β receptors on the dendritic cells is critical for their homeostasis and expansion. J. Immunol. 175, 6997–7002 (2005).
Heo, S. K. et al. LIGHT enhances the bactericidal activity of human monocytes and neutrophils via HVEM. J. Leuk. Biol. 79, 330–338 (2006).
Fan, Z. et al. NK-cell activation by LIGHT triggers tumor-specific CD8+ T-cell immunity to reject established tumors. Blood 107, 1342–1351 (2006). References 29, 32, 75 and 76 illuminate the co-stimulatory effects of HVEM ligation on DCs, B cells, monocytes, neutrophils, and NK cells. HVEM was shown to synergize with other signals from, for example, antigen receptors or CD40L, to induce greater proliferation and cytokine production in these cell types.
Wang, J. et al. The critical role of LIGHT, a TNF family member, in T cell development. J. Immunol. 167, 5099–5105 (2001).
Wang, J. et al. The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT. J. Clin. Invest. 108, 1771–1780 (2001).
Wang, J. et al. Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy. J. Clin. Invest. 113, 826–835 (2004). References 35 and 78 show how constitutive T-cell expression of LIGHT results in multiple organ inflammation and autoimmunity. Reference 79 shows that constitutive LIGHT expression can also lead to elevated serum IgA and nephropathy, and that these specific effects were dependent on LTβR, and not HVEM.
Wang, J. & Fu, Y. X. LIGHT (a cellular ligand for herpes virus entry mediator and lymphotoxin receptor)-mediated thymocyte deletion is dependent on the interaction between TCR and MHC/self-peptide. J. Immunol. 170, 3986–3993 (2003).
Ye, Q. et al. Modulation of LIGHT–HVEM costimulation prolongs cardiac allograft survival. J. Exp. Med. 195, 795–800 (2002).
Tamada, K. et al. Cutting edge: selective impairment of CD8+ T cell function in mice lacking the TNF superfamily member LIGHT. J. Immunol. 168, 4832–4835 (2002).
Scheu, S. et al. Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin β in mesenteric lymph node genesis. J. Exp. Med. 195, 1613–1624 (2002).
Liu, J. et al. LIGHT-deficiency impairs CD8+ T cell expansion, but not effector function. Int. Immunol. 15, 861–870 (2003). References 81–84 describe four groups of independently generated LIGHT-deficient mice, all showing defects in T-cell activation and T-cell-mediated inflammatory responses.
Deppong, C. et al. Cutting edge: B and T lymphocyte attenuator and programmed death receptor-1 inhibitory receptors are required for termination of acute allergic airway inflammation. J. Immunol. 176, 3909–3913 (2006). Shows that BTLA deficiency results in prolonged airway inflammation following challenge, indicating a role for BTLA in the termination of inflammatory responses.
Tao, R. et al. Differential effects of B and T lymphocyte attenuator and programmed death-1 on acceptance of partially versus fully MHC-mismatched cardiac allografts. J. Immunol. 175, 5774–5782 (2005). Shows that mice deficient in either BTLA or HVEM have similarly increased hyperinflammatory responses to a cardiac graft that differs from the host at only the MHC class II alleles. This increased inflammation probably reflects defective BTLA inhibition of T-cell activation.
Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003).
Vijayakrishnan, L. et al. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity 20, 563–575 (2004).
Langstein, J. et al. CD137 (ILA/4–1BB), a member of the TNF receptor family, induces monocyte activation via bidirectional signaling. J. Immunol. 160, 2488–2494 (1998).
Wiley, S. R., Goodwin, R. G. & Smith, C. A. Reverse signaling via CD30 ligand. J. Immunol. 157, 3635–3639 (1996).
van Essen, D., Kikutani, H. & Gray, D. CD40 ligand-transduced co-stimulation of T cells in the development of helper function. Nature 378, 620–623 (1995).
Suzuki, I. & Fink, P. J. Maximal proliferation of cytotoxic T lymphocytes requires reverse signaling through Fas ligand. J. Exp. Med. 187, 123–128 (1998).
Stuber, E. et al. Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells. Immunity 2, 507–521 (1995).
Kirchner, S. et al. LPS resistance in monocytic cells caused by reverse signaling through transmembrane TNF (mTNF) is mediated by the MAPK/ERK pathway. J. Leuk. Biol. 75, 324–331 (2004).
Zhai, Y. et al. LIGHT, a novel ligand for lymphotoxin β receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer. J. Clin. Invest. 102, 1142–1151 (1998).
Gough, S. C., Walker, L. S. & Sansom, D. M. CTLA4 gene polymorphism and autoimmunity. Immunol. Rev. 204, 102–115 (2005).
Okazaki, T. & Wang, J. PD-1/PD-L pathway and autoimmunity. Autoimmunity 38, 353–357 (2005).
Chadha, S. et al. Haplotype analysis of tumour necrosis factor receptor genes in 1p36: no evidence for association with systemic lupus erythematosus. Eur. J. Hum. Genet. 14, 69–78 (2006).
La, S. et al. Herpes simplex virus type 1 glycoprotein D inhibits T-cell proliferation. Mol. Cell 14, 398–403 (2002).
Krummenacher, C. et al. Structure of unliganded HSV gD reveals a mechanism for receptor-mediated activation of virus entry. EMBO J. 24, 4144–4153 (2005).
Benedict, C. A. et al. Cutting edge: a novel viral TNF receptor superfamily member in virulent strains of human cytomegalovirus. J. Immunol. 162, 6967–6970 (1999).
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The authors would like to thank M. Hurchla, P. Wilker and A.V. Miletic Šedý for critical reading of the manuscript.
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Glossary
- Co-stimulatory signals
-
Optimal signalling through the T-cell or B-cell receptor complex requires accessory cell-surface molecules, such as CD28, inducible T-cell co-stimulator (ICOS) and members of the tumour-necrosis factor receptor family. These co-stimulatory signals synergize with primary signals that promote the proliferation and effector function of these lymphocytes and of other cell types.
- Immunoglobulin superfamily
-
A family of proteins that contain immunoglobulin domains. Immunoglobulin domains themselves are made up of 7–9 β-strands and often mediate protein–protein interactions.
- T-helper (TH) cells
-
TH cells secrete distinct patterns of cytokines after activation, which occurs through ligation of their T-cell receptors with their cognate ligands (peptide–MHC complexes), together with recognition of the appropriate co-stimulatory molecules. Undifferentiated TH0 cells differentiate (or polarize) into TH1 or TH2 cells, depending on the cytokines and co-stimulatory molecules presented to them by antigen-presenting cells.
- Tetramers
-
A staining reagent consisting of the biotinylated recombinant extracellular domain of a cell-surface receptor bound onto a fluorochrome-coupled streptavidin support. The resulting tetramer can be used to identify cells expressing ligands for the cell-surface receptor. Tetramers are commonly made from MHC-class-I complexes to identify CD8+ T-cell populations.
- Retroviral cDNA library
-
A eukaryotic RNA-transcript-expression library in which mouse cDNA is introduced into a retroviral construct and packaged into a retrovirus capable of a single infection. This retrovirus is then stably introduced into cell lines in order to clonally express all cDNAs, which are then screened for clones of interest.
- Surface-plasmon resonance
-
A technique used to measure molecular interactions by observing how much of an input molecule (for example, a protein) is bound to a chip adsorbed with another molecule. The amount of bound input is directly proportional to the change in the light reflected off the adsorbed chip, which is specifically measured. This technique can be used to calculate single-molecule affinities as well as binding on and off rates.
- Size exclusion chromatography
-
A technique used to separate solution-phase molecular complexes on the basis of their hydrodynamic radius, which is related to their overall molecular weight. This technique is also useful for isolating non-covalently bound complexes.
- Germinal centre
-
Structures located in peripheral lymphoid tissues such as the spleen. They are sites of B-cell proliferation and selection of clones that produce antigen-specific antibodies of higher affinity.
- Protein kinase B
-
A serine/threonine kinase that is activated following recruitment to the lipid membrane by phosphatidylinositol 3-kinase (PI3K) and phosphorylation by 3-phosphoinositide-dependent protein kinase (PDK), and can regulate cell division and cell survival through actions on cell-cycle inhibitors and both pro- and anti-apoptotic members of the B-cell lymphoma 2 (BCL2) family.
- Immunoreceptor tyrosine-based inhibitory motif
-
(ITIM). This motif is present in the cytoplasmic domain of several inhibitory receptors. After ligand binding, ITIMs are tyrosine phosphorylated and recruit inhibitory phosphatases.
- Nuclear factor-κB
-
A family of transcription factors that are important for pro-inflammatory and anti-apoptotic responses. They are activated by the phosphorylation and subsequent ubiquitin-dependent proteolytic degradation of inhibitory proteins following mitogenic signals.
- Activator protein 1
-
A transcription-factor complex composed of a heterodimer of JUN and FOS subunits that is necessary for the induction of interleukin-2 transcription in T cells. JUN and FOS subunits are members of a family of leucine-zipper-containing proteins that are induced by mitogenic stimuli.
- Mixed lymphocyte reaction
-
A tissue-culture technique for testing T-cell reactivity. The proliferation of one population of T cells, induced by exposure to inactivated MHC-mismatched stimulator cells, is determined by measuring the incorporation of 3H-thymidine into the DNA of dividing cells.
- IgA nephropathy
-
A form of glomerulonephritis in which defective IgA transport to the gut lumen leads to increased serum IgA levels and renal deposition.
- Concanavalin A
-
A plant lectin that functions as a T-cell mitogen.
- Experimental autoimmune encephalomyelitis
-
An experimental model of multiple sclerosis that is induced by immunization of susceptible animals with myelin-derived antigens such as myelin basic protein, proteolipid protein or myelin oligodendrocyte glycoprotein.
- Polymorphisms
-
Single-nucleotide differences in the sequence of genes that represent allelic variants. These differences might lead to altered structure and/or altered expression of gene products, ultimately leading to pathology.
- Systemic lupus erythematosus
-
(SLE). An autoimmune disease in which autoantibodies that are specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, especially in the kidneys. Patients with SLE generally have abnormal B- and T-cell function.
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Murphy, K., Nelson, C. & Šedý, J. Balancing co-stimulation and inhibition with BTLA and HVEM. Nat Rev Immunol 6, 671–681 (2006). https://doi.org/10.1038/nri1917
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DOI: https://doi.org/10.1038/nri1917
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