HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160

Liu, Weifeng; Chou, Ting-Fang; Garrett-Thomson, Sarah C.; Seo, Goo-Young; Fedorov, E.V.; Ramagopal, U.A.; Bonanno, J.B.; Wang, Qingyang; Kim, Kenneth S.; Garforth, S.; Kakugawa, Kiyokazu; Cheroutre, Hilde; Kronenberg, Mitchell; Almo, Steven C.

doi:10.1084/jem.20211112

Cited by 23 publications

(20 citation statements)

References 49 publications

(72 reference statements)

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“…In contrast, the relative low affinity of HVEM for BTLA and CD160 requires cell contact to activate signaling. analysis revealed BTLA and CD160 bind overlapping sites on HVEM but occupy distinct domains from LIGHT and LTα, creating variations in ligand-receptor complexes and consequences for signaling pathways (Carfi et al, 2001;Compaan et al, 2005;Liu et al, 2014;Liu et al, 2021). Innate effector cells such as NK cells and γδT cells coexpress HVEM, CD160, and BTLA with a high CD160:BTLA ratio.…”

Section: Light-hvem-b and T Lymphocyte Attenuator (Btla) Signaling Ne...mentioning

confidence: 99%

Realigning the LIGHT signaling network to control dysregulated inflammation

Ware

Croft

Neil³

2022

Journal of Experimental Medicine

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Advances in understanding the physiologic functions of the tumor necrosis factor superfamily (TNFSF) of ligands, receptors, and signaling networks are providing deeper insight into pathogenesis of infectious and autoimmune diseases and cancer. LIGHT (TNFSF14) has emerged as an important modulator of critical innate and adaptive immune responses. LIGHT and its signaling receptors, herpesvirus entry mediator (TNFRSF14), and lymphotoxin β receptor, form an immune regulatory network with two co-receptors of herpesvirus entry mediator, checkpoint inhibitor B and T lymphocyte attenuator, and CD160. Deciphering the fundamental features of this network reveals new understanding to guide therapeutic development. Accumulating evidence from infectious diseases points to the dysregulation of the LIGHT network as a disease-driving mechanism in autoimmune and inflammatory reactions in barrier organs, including coronavirus disease 2019 pneumonia and inflammatory bowel diseases. Recent clinical results warrant further investigation of the LIGHT regulatory network and application of target-modifying therapeutics for disease intervention.

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Section: Light-hvem-b and T Lymphocyte Attenuator (Btla) Signaling Ne...mentioning

confidence: 99%

Realigning the LIGHT signaling network to control dysregulated inflammation

Ware

Croft

Neil³

2022

Journal of Experimental Medicine

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“…We found that L52 and M60 play an important role in the binding interface for the complete HVEM molecule (Fig. S9), while other experimentally determined amino-acid residues (Liu et al, 2021), such as H48 and L56, are in their vicinity an may play the role to stabilize the local structure of HVEM, rather than playing role in formation of the direct interactions. It is further confirmed by the observation of the Liu et al that only pairwise mutagenesis of the H48, L52, and L56 has the observable effect on the LIGHT binding.…”

Section: Discussionmentioning

confidence: 84%

Computational Design of a Highly-Specific HVEM-Based Inhibitor of LIGHT Protein

Ciura,

Smardz,

Krupa

et al. 2023

Preprint

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MotivationHVEM-LIGHT binding regulates the immune system response in various ways: it co-stimulates T cell proliferation; promotes B cell differentiation and secretion of immunoglobulins; and enhances dendritic cell maturation. Strong and prolonged stimulation of T cells to proliferate causes high levels of IFN–γ, which leads to chronic inflammation and is the reason for various autoimmune diseases. Therefore, blocking HVEM-LIGHT interaction may be a way to cure these diseases and prevent adverse reaction in organ and tissue transplantation.ResultsIn this work, we designed 62 peptides based on the CRDs of the HVEM structure, differentiating in the number and combination of disulfide bonds present. Based on extensive all-atom MD simulations in state-of-the-art force fields, followed by MM-GBSA binding energy estimation, we selected the most promising CRD2 variants interacting with LIGHT. Several point mutations of these variants provided us with the most strongly binding moiety: the CRD2 with a single disulfide bond (C58-C73) and K54E substitution. This result was supprased only by the truncated variants of CRD2(39-73) with the same disulfide bond present. The binding mechanism was investigated by the use of steered MD simulations, which showed the increased binding affinity of the abovementioned variants, while experimental circular dichroism was used to determine their structural properties.Availability and ImplementationThree PDB models of the LIGHT inhibitors: PM0084527, PM0084528, and PM0084592.Contactpkrupa@ifpan.edu.plSupplementary informationOnline supplementary data is available at: .

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“…CD160 has a lower affinity for HVEM than BTLA ( 200 ). CD160–HVEM interactions weakened TCR-mediated signal transduction and suppressed T cell activation ( 202 , 203 ).…”

Section: The Ig-sfmentioning

confidence: 99%

T cell co-stimulatory and co-inhibitory pathways in atopic dermatitis

Zheng

Shi²,

Zou³

2023

Front. Immunol.

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The use of immune checkpoint inhibitors (ICIs) targeting the T cell inhibitory pathways has revolutionized cancer treatment. However, ICIs might induce progressive atopic dermatitis (AD) by affecting T cell reactivation. The critical role of T cells in AD pathogenesis is widely known. T cell co-signaling pathways regulate T cell activation, where co-signaling molecules are essential for determining the magnitude of the T cell response to antigens. Given the increasing use of ICIs in cancer treatment, a timely overview of the role of T cell co-signaling molecules in AD is required. In this review, we emphasize the importance of these molecules involved in AD pathogenesis. We also discuss the potential of targeting T cell co-signaling pathways to treat AD and present the unresolved issues and existing limitations. A better understanding of the T cell co-signaling pathways would aid investigation of the mechanism, prognosis evaluation, and treatment of AD.

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HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160

Cited by 23 publications

References 49 publications

Realigning the LIGHT signaling network to control dysregulated inflammation

Realigning the LIGHT signaling network to control dysregulated inflammation

Computational Design of a Highly-Specific HVEM-Based Inhibitor of LIGHT Protein

T cell co-stimulatory and co-inhibitory pathways in atopic dermatitis

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