Structural basis for co-stimulation by the human CTLA-4/B7-2 complex

Schwartz, Jess D.; Zhang, Xuewu; Fedorov, A.A.; Nathenson, Stanley G.; Almo, Steven C.

doi:10.1038/35069112

Cited by 317 publications

(339 citation statements)

References 31 publications

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“…Interestingly, Tyr-31 in human CD86 is substituted by phenylalanine without any apparent change in the ligand binding affinities (18,19,24), whereas the Y31A substitution completely abolishes the binding of hCD80 to both CD28 and CTLA-4 (20). The present data demonstrate that the Y31H substitution permits retention of the interaction with CTLA-4, at least when present in the context of the shuffled CTLA-4BP sequence, whereas this mutation appears to contribute to the loss of binding to CD28.…”

Section: Discussionmentioning

confidence: 60%

Chimeric Co-stimulatory Molecules That Selectively Act through CD28 or CTLA-4 on Human T Cells

Lazetic

Leong

Chang

et al. 2002

Journal of Biological Chemistry

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CD28 and CTLA-4 (CD152) play a pivotal role in the regulation of T cell activation. Upon ligation by CD80 (B7-1) or CD86 (B7-2), CD28 induces T cell proliferation, cytokine production, and effector functions, whereas CTLA-4 signaling inhibits expansion of activated T cells and induces tolerance. Therefore, we hypothesized that co-stimulatory molecules that preferentially bind CD28 or CTLA-4 would have dramatically altered biological properties. We describe directed molecular evolution of CD80 genes derived from human, orangutan, rhesus monkey, baboon, cat, cow, and rabbit by DNA shuffling and screening. In contrast to wild-type CD80, the evolved co-stimulatory molecules, termed CD28-binding protein (CD28BP) and CTLA-4-binding protein (CTLA-4BP), selectively bind to CD28 or CTLA-4, respectively. Furthermore, CD28BP has improved capacity to induce human T cell proliferation and interferon-␥ production compared with wild-type CD80. In contrast, CTLA-4BP inhibited human mixed leukocyte reaction (MLR) and enhanced interleukin 10 production in MLR, supporting a role for CTLA-4BP in inducing T cell anergy and tolerance. In addition, co-stimulation of purified human T cells was significantly suppressed when CTLA-4BP was cotransfected with either CD80 or CD28BP. The amino acid sequences of CD28BP and CTLA-4BP were 61 and 96% identical with that of human CD80 and provide insight into the residues that are critical in the ligand binding. These molecules provide a new approach to characterization of CD28 and CTLA-4 signals and to manipulation of the T cell response.T cell response is dependent on complex integration of antigen-specific and nonspecific extracellular and intracellular signals. The specificity of the response is determined by recognition of an antigenic peptide in the context of major histocompatibility complex on the plasma membrane of antigen-presenting cells, such as monocytes, dendritic cells, Langerhans cells, or primed B cells. However, a second signal, mediated by co-stimulatory molecules expressed on antigenpresenting cells, is required for induction of a complete T cell response (1-3). The most extensively studied co-stimulatory molecules are CD80 (B7-1) and CD86 (B7-2), which bind the CD28 and CTLA-4 (CD152) ligands expressed on CD4 ϩ and CD8 ϩ T cells. Additional co-stimulatory molecule-ligand pairs such as ICOS-B7-H and PD1-PDL have recently been identified, further illustrating the complexity of the signals that regulate the function of T cells (1-3). Co-stimulatory signal in addition to the T cell receptor signal is a prerequisite for induction of optimal T activation, proliferation, cytokine production, and effector functions.The functional characterization of CD80, CD86, CD28, and CTLA-4 has also illustrated the delicate balance between positive and negative signals mediated through CD28 and CTLA-4, respectively. Upon ligation by CD80 or CD86, CD28 synergizes with T cell receptor signaling to induce activation of both CD4 ϩ and CD8 ϩ T cells (4 -7), whereas CTLA-4 ligation inhibits expansion of...

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Section: Discussionmentioning

confidence: 60%

Chimeric Co-stimulatory Molecules That Selectively Act through CD28 or CTLA-4 on Human T Cells

Lazetic

Leong

Chang

et al. 2002

Journal of Biological Chemistry

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“…1c). In B7-2 this cavity is utilized to bind CTLA4 (29). The IgV domains of B7-2 and MOG that are both encoded within the MHC show sequence identities of 27%, but the amino acids that contribute to the formation of the cavity are not conserved between MOG and B7-2.…”

Section: Resultsmentioning

confidence: 99%

Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein

Breithaupt

Schubart

Zander

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

121

120

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M ultiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) associated with autoaggressive T and B cell responses to various myelin proteins. Myelin oligodendrocyte glycoprotein (MOG) was identified as a candidate autoantigen in MS because it induces a demyelinating antibody response in laboratory animals with experimental autoimmune encephalomyelitis (EAE), an animal model of MS (1). MOG is a quantitatively minor type I transmembrane CNS protein of unknown function with a single extracellular Ig-like domain (2). In contrast to other CNS proteins, MOG is found only in mammals and is highly conserved across species. It is expressed exclusively in the CNS by myelin-forming oligodendrocytes and is preferentially localized at the outermost surface of the myelin sheath thus directly exposed to autoantibodies in the extracellular milieu. MOG is the only antigen that can induce both a pathogenic demyelinating autoantibody response and an encephalitogenic T cell response in experimental animals (3). In MOG-induced EAE this combination of immune effector mechanisms reproduces the demyelinating pathology seen in the majority of patients with MS. The clinical relevance of autoimmune responses to MOG in MS is supported by reports that MS is associated with enhanced MOG-specific T and B cell responses and by the identification of MOG-specific antibodies associated with myelin debris in actively demyelinating MS lesions (4). Experimental evidence indicates that the autoantibody response to MOG is heterogeneous; demyelinating MOG-specific autoantibodies recognize purely conformation-dependent epitopes whereas MOG peptide-specific antibodies fail to recognize the native protein (5-7). To examine the structural basis of the pathogenic autoantibody response to MOG we determined the crystal structures of the extracellular domain of rat MOG (residues 1-126, MOG Igd ) and a complex of MOG Igd with the chimeric antigen-binding fragment (Fab) of the demyelinating MOG-specific monoclonal antibody 8-18C5 (8). Materials and Methods Preparation of Recombinant MOG Igd and the MOG Igd -(8-18C5)-FabComplex. The cDNA of the extracellular domain of rat MOG (residues 1-125) was subcloned into the His-tag expression vector pQE-12. The protein was overexpressed in inclusion bodies in Escherichia coli, refolded, and further purified by nickel-nitrilotriacetic acid affinity chromatography and gel filtration. Selenomethionine (SeMet)-labeled protein was produced in the methionine-auxotrophic E. coli strain B834(DE3) and grown in minimal medium with SeMet (0.3 mM) substituted for methionine. The cDNA of the variable domains of the mouse monoclonal antibody 8-18C5 was subcloned into the expression vector pASK107, yielding the chimeric (8-18C5)-Fab composed of the 8-18C5 variable domains, the human IgG constant domains, and the Strep tag II fused to the C terminus of the heavy chain (9, 10). (8-18C5)-Fab was produced by periplasmic secretion in E. coli and purified by streptavidin affinity chromatogr...

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“…Additional studies in which the pathway is inhibited-either by blocking proteins or by gene ablation-support the TIGIT-PVR interaction as being important for setting the threshold for T-cell responses in both secondary lymph organs and mucosal sites (31,32). The predominant immuno-coreceptors on T cells are CTLA-4 and CD28, which engage the same ligands, B7-1 and B7-2, on antigen-presenting cells such as DCs (28,29,33); however, additional receptors, such as PD-1 and ICOS, have emerged as important receptors in the immune system to fine-tune T-cell effector functions and maintain T-cell tolerance (34). PVR, together with TIGIT and other PVRfamily members, CD226 and CD96, similarly regulate immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, this work suggests that weaker preformed cis-dimers of TIGIT on the cell surface are required for cis-trans receptor oligomerization that is necessary for PVR signaling into primary cells. A similar coupling of cis-trans dimerization has been investigated for the covalent cishomodimers in the CTLA-4-B7-1/2 complexes and for noncovalent cis-homodimers in cadherins as well as in the CAR-JAML complex and the Necl-SynCAM2 (12,13,25,(27)(28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell–cell adhesion and signaling mechanism that requires cis-trans receptor clustering

Stengel¹,

Harden-Bowles²,

Yu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

159

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Nectins (nectin1-4) and Necls ] are Ig superfamily cell adhesion molecules that regulate cell differentiation and tissue morphogenesis. Adherens junction formation and subsequent cell-cell signaling is initiated by the assembly of higher-order receptor clusters of cognate molecules on juxtaposed cells. However, the structural and mechanistic details of signaling cluster formation remain unclear. Here, we report the crystal structure of poliovirus receptor (PVR)/Nectin-like-5/CD155) in complex with its cognate immunoreceptor ligand T-cell-Ig-and-ITIM-domain (TIGIT). The TIGIT/ PVR interface reveals a conserved specific "lock-and-key" interaction. Notably, two TIGIT/PVR dimers assemble into a heterotetramer with a core TIGIT/TIGIT cis-homodimer, each TIGIT molecule binding one PVR molecule. Structure-guided mutations that disrupt the TIGIT/ TIGIT interface limit both TIGIT/PVR-mediated cell adhesion and TIGIT-induced PVR phosphorylation in primary dendritic cells. Our data suggest a cis-trans receptor clustering mechanism for cell adhesion and signaling by the TIGIT/PVR complex and provide structural insights into how the PVR family of immunoregulators function.N ectins (nectin1-4) and nectin-like (Necl1-5) molecules are members of the large Ig superfamily (IgSF) of cell-surface receptors that play central roles in cell adhesion, cell movement, proliferation, and survival and contribute to the morphogenesis and differentiation of many cell and tissue types by inducing an intracellular signaling cascade (1-5). Nectins and Necls can function as both ligands and receptors and therefore are able to signal bidirectionally into juxtaposed cells (3,6). To mediate the formation of cell adherens junctions, a model suggests that the extracellular domains of these molecules form ligand-dependent homo-or heterodimers in trans (between molecules located on the same or opposite cell surfaces, respectively) and lateral homodimers in cis, creating a tight network of nectin zippers between juxtaposed cells (7,8). To date, structural and functional studies suggest a mechanism whereby the cis-homodimerization of a receptor on the same cell surface is followed by the formation of a trans-dimer between juxtaposed cells using identical protein interfaces. This assembly is noteworthy because it requires a rearrangement and breakup of the cis-homodimer followed by a transdimerization across the adherens junction. The cis-trans clustering is then initiated through another unknown protein interface, likely involving a different receptor domain.Several high-affinity homophilic trans-interactions have been described in detail for nectins/Necls and similar molecules (8-13). However, the structure and function of the presumably weaker lateral homophilic cis-dimers in cell adhesion and their role in intracellular signaling is not known. Because all structures solved to date are homodimers, it is unclear if they represent the cisor the trans-state. Thus, the question of how cis-trans heterodimerization drives cell adhesion and intracellular sign...

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Structural basis for co-stimulation by the human CTLA-4/B7-2 complex

Cited by 317 publications

References 31 publications

Chimeric Co-stimulatory Molecules That Selectively Act through CD28 or CTLA-4 on Human T Cells

Chimeric Co-stimulatory Molecules That Selectively Act through CD28 or CTLA-4 on Human T Cells

Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein

Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell–cell adhesion and signaling mechanism that requires cis-trans receptor clustering

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