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Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering.

ABSTRACT: The inhibitory T-cell surface-expressed receptor, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), which belongs to the class of cell surface proteins phosphorylated by extrinsic tyrosine kinases that also includes antigen receptors, binds the related ligands, B7-1 and B7-2, expressed on antigen-presenting cells. Conformational changes are commonly invoked to explain ligand-induced "triggering" of this class of receptors. Crystal structures of ligand-bound CTLA-4 have been reported, but not the apo form, precluding analysis of the structural changes accompanying ligand binding. The 1.8-Å resolution structure of an apo human CTLA-4 homodimer emphasizes the shared evolutionary history of the CTLA-4/CD28 subgroup of the immunoglobulin superfamily and the antigen receptors. The ligand-bound and unbound forms of both CTLA-4 and B7-1 are remarkably similar, in marked contrast to B7-2, whose binding to CTLA-4 has elements of induced fit. Isothermal titration calorimetry reveals that ligand binding by CTLA-4 is enthalpically driven and accompanied by unfavorable entropic changes. The similarity of the thermodynamic parameters determined for the interactions of CTLA-4 with B7-1 and B7-2 suggests that the binding is not highly specific, but the conformational changes observed for B7-2 binding suggest some level of selectivity. The new structure establishes that rigid-body ligand interactions are capable of triggering CTLA-4 phosphorylation by extrinsic kinase(s).

SUBMITTER: Yu C

PROVIDER: S-EPMC3057841 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering.

Yu Chao C Sonnen Andreas F-P AF George Roger R Dessailly Benoit H BH Stagg Loren J LJ Evans Edward J EJ Orengo Christine A CA Stuart David I DI Ladbury John E JE Ikemizu Shinji S Gilbert Robert J C RJ Davis Simon J SJ

The Journal of biological chemistry 20101214 8

The inhibitory T-cell surface-expressed receptor, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), which belongs to the class of cell surface proteins phosphorylated by extrinsic tyrosine kinases that also includes antigen receptors, binds the related ligands, B7-1 and B7-2, expressed on antigen-presenting cells. Conformational changes are commonly invoked to explain ligand-induced "triggering" of this class of receptors. Crystal structures of ligand-bound CTLA-4 have been reported, but not ...[more]

PMID: 21156796

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Project description:Immune checkpoint regulators, cytotoxic T lymphocyte antigen 4 (CTLA-4) and the programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) have emerged as promising new targets for cancer therapeutics. While tumor expression of PD-L1 has been shown to have objective responses to anti-PD-L1 immunotherapies, the clinical implications of CTLA-4 expression in tumor cells or immune cells in the tumor microenvironment is still controversial. We investigated the expression of CTLA-4 and PD-L1 in human breast tumors and provided a scoring system for the systematic evaluation of CTLA-4 staining.Immunohistochemical staining for PD-L1 and CTLA-4 expression was performed on a tissue microarray of 102 cores, which included normal and neoplastic breast tissues. Neoplastic cores were divided into four groups: Ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC) and invasive tubular carcinoma (ITC). PD-L1 and CTLA-4 expressions were scored based on a system which accounted for the percentage and intensity of positivity and results provided in conjunction with available clinical and demographic data.Overall, CTLA-4 was over-expressed in 49 of 93 (52.7%) breast tumors. Subcategorically, CTLA-4 was positive in 3 of 8 (37.5%) ductal carcinoma in situ, 40 of 73 (55%) of invasive ductal carcinomas, 4 of 10 (40%) of invasive lobular carcinomas and 2 of 2 (100%) of invasive tubular carcinomas. All 6 normal breast tissues were interpreted as negative for CTLA-4 staining. Only 4.1% of the invasive ductal carcinomas were positive for PD-L1 reactivity and the remaining carcinomas stained negative.This study shows a significant overexpression of CTLA-4 in >50% of breast carcinomas with no such overexpression of CTLA-4 in benign breast tissues. PDL-1 staining is seen in only a small number of invasive ductal carcinomas (4.1%). These findings suggest the need for further investigation of anti-CTLA-4 and anti-PD-L1 immunotherapies and their efficacy in the treatment of breast carcinomas with overexpression of these immune modulators. In addition, the proposed scoring system will facilitate a more systematic correlation between tumor reactivity and clinical outcome which can be applied to all intracytoplasmic tumor markers.

Project description:BackgroundCytotoxic T lymphocyte-associated antigen-4-Ig (CTLA-4-Ig) competes with CD28 for binding CD80/CD86 on antigen-presenting cells (APCs) to limit T cell activation. B cells are believed to be important APCs in the pathogenesis of autoimmune diseases and express CD80/CD86 after activation; however, relatively little is known about the effect of CTLA-4-Ig on B cells. This study tested the impact of CTLA-4-Ig on human B cell responses.MethodsHuman blood B cells were purified from healthy donors and activated in the presence of CTLA-4-Ig or the L6-Ig control protein in vitro. RT-q-PCR and immunofluorescence staining were performed to detect activation marker expression. ELISA was conducted to measure cytokine secretion. The CD80/CD86 levels on the surface of the memory B cells in the blood of 18 patients with rheumatoid arthritis (RA) were detected using immunofluorescence staining.ResultsCTLA-4-Ig suppressed the expression of Staphylococcus aureus (SAC)-induced CD80, CD86, TNFA, and IL6 in human B cells at the transcriptional level. Furthermore, CTLA-4-Ig concomitantly decreased SAC-induced CD80/CD86 surface expression on and TNF-α and IL-6 secretion from B cells. On the other hand, T cell-dependent (TD) stimulation-induced B cell activation, proliferation, plasma cell differentiation, and antibody secretion were not affected by CTLA-4-Ig. As expected, TD stimulation-induced surface CD80 was hindered by CTLA-4-Ig. Notably, a blockade of CD80/CD86 on the surface of the memory B cells was observed in the patients with RA after abatacept (CTLA-4-Ig) treatment. In a portion of the RA patients, restoration of CD80/CD86 staining on the surface of the memory B was detected starting in the 3rd month of abatacept treatment. Interestingly, the surface levels of CD80/CD86 on the patients' memory B cells positively correlated with disease activity.ConclusionsWe found that CTLA-4-Ig directly suppressed SAC-induced B cell activation in vitro. Obstruction of CD80 and CD86 on the surface of the memory B cells was detected in the RA patients after abatacept treatment. Blocking CD80/CD86 on B cells by CTLA-4-Ig may hinder T cell activation and associated with the disease activity of RA in vivo. Our findings indicate that CTLA-4-Ig may regulate humoral responses by modulating B cell activation and interfering T cell-B cell interaction.

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Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering.

Publications

Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering.

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