Harnessing proteases for T regulatory cell immunotherapy

Amarnath, Shoba; Brown, Marnie L.

doi:10.1002/eji.201948270

Cited by 4 publications

(4 citation statements)

References 83 publications

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“…LGMN is a newly discovered member of the C13 family of lysosomal cysteine proteases and plays an important role in the progression of cancer, modulation of immunity, such as antigen processing and TLR processing, and neurodegenerative diseases by cleaving or degrading specific proteins. 18,19,39 Macrophage-derived LGMN promotes the development of thoracic aortic dissection and cardiac remodeling after myocardial infarction. 20,21 LGMN is also highly expressed in T cells, and its expression is further upregulated upon T-cell stimulation.…”

Section: Discussionmentioning

confidence: 99%

“…17 In the immune system, LGMN is found in dendritic cells, B cells, and macrophages and plays a role in antigen and TLR (toll-like receptor) processing, implying its importance in immunity. 18,19 Macrophage-derived LGMN aggravates cardiac remodeling in postacute myocardial infarction and promotes the development of thoracic aortic dissection. 20,21 Recently, LGMN was reported to be highly expressed in T cells, further increasing upon CD46 costimulation.…”

mentioning

confidence: 99%

“…22 Interestingly, LGMN is also expressed in human Tregs, and blocking LGMN can enhance Treg function in both human and mouse CD4+ T cells. 19,23 However, the pathophysiological significance and T cell–specific function of LGMN in cardiovascular disease, especially in hypertension, are largely unknown.…”

mentioning

confidence: 99%

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CD4+ T-Cell Legumain Deficiency Attenuates Hypertensive Damage via Preservation of TRAF6

He,

Zou,

et al. 2024

Circulation Research

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BACKGROUND: T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of hypertension remains unclear. METHODS: Peripheral blood samples were collected from patients with hypertension, and CD4+ T cells were sorted for gene expression and Western blotting analysis. TLGMNKO (T cell–specific LGMN-knockout) mice (Lgmn f/f /CD4 Cre ), regulatory T cell (Treg)–specific LGMN-knockout mice (Lgmn f/f /Foxp3 YFP Cre ), and RR-11a (LGMN inhibitor)–treated C57BL/6 mice were infused with Ang II (angiotensin II) or deoxycorticosterone acetate/salt to establish hypertensive animal models. Flow cytometry, 4-dimensional label-free proteomics, coimmunoprecipitation, Treg suppression, and in vivo Treg depletion or adoptive transfer were used to delineate the functional importance of T-cell LGMN in hypertension development. RESULTS: LGMN mRNA expression was increased in CD4+ T cells isolated from hypertensive patients and mice, was positively correlated with both systolic and diastolic blood pressure, and was negatively correlated with serum IL (interleukin)-10 levels. TLGMNKO mice exhibited reduced Ang II–induced or deoxycorticosterone acetate/salt–induced hypertension and target organ damage relative to WT (wild-type) mice. Genetic and pharmacological inhibition of LGMN blocked Ang II–induced or deoxycorticosterone acetate/salt–induced immunoinhibitory Treg reduction in the kidneys and blood. Anti-CD25 antibody depletion of Tregs abolished the protective effects against Ang II–induced hypertension in TLGMNKO mice, and LGMN deletion in Tregs prevented Ang II–induced hypertension in mice. Mechanistically, endogenous LGMN impaired Treg differentiation and function by directly interacting with and facilitating the degradation of TRAF6 (tumor necrosis factor receptor–associated factor 6) via chaperone-mediated autophagy, thereby inhibiting NF-κB (nuclear factor kappa B) activation. Adoptive transfer of LGMN-deficient Tregs reversed Ang II–induced hypertension, whereas depletion of TRAF6 in LGMN-deficient Tregs blocked the protective effects. CONCLUSIONS: LGMN deficiency in T cells prevents hypertension and its complications by promoting Treg differentiation and function. Specifically targeting LGMN in Tregs may be an innovative approach for hypertension treatment.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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CD4+ T-Cell Legumain Deficiency Attenuates Hypertensive Damage via Preservation of TRAF6

He,

Zou,

et al. 2024

Circulation Research

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“…Asparaginyl endopeptidase (AEP) could cleave FOXP3 that results in instability of FOXP3 in Tbet + iTreg and therefore decreased suppressive functions of Tregs in mice. Inhibition of AEP can stabilize FOXP3 and enhance Tregs function [81][82][83][84].…”

Section: Posttranslational Modifications Of Foxp3mentioning

confidence: 99%

Transcriptional and posttranslational regulation of Th17/Treg balance in health and disease

et al. 2021

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Regulatory T (Treg) cells and T helper type 17 (Th17) cells play important roles in adaptive immune responses, antagonizing each other in immune disorders. Th17/Treg balance is critical to maintaining the immune homeostasis of human bodies and is tightly regulated under healthy conditions. The transcription factors that are required for driving Th17 and Treg cell lineages differentiation respectively, RORγt and FOXP3 are tightly regulated under different tissue microenvironment, especially the transcriptional induction, posttranslational modifications, and dynamic enzymatic cofactors binding. The imbalance caused by alteration of the quantity or properties of RORγt + Th17 or FOXP3 + Treg can contribute to inflammatory disorders in humans. Restoring Th17/Treg balance by modifying the enzymatic activities of RORγt and FOXP3 binding partners may be therapeutically applied to treat severe immune disorders. In this review, we focus on the transcriptional and posttranslational regulations of Th17/Treg balance, immune disorders caused by Th17/Treg imbalance, and new therapeutic strategies for restoring immune homeostasis.

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DON/DRP‐104 as potent serine protease inhibitors implicated in SARS‐CoV‐2 infection: Comparative binding modes with human TMPRSS2 and novel therapeutic approach

Oduro‐Kwateng,

Soliman

2024

J of Cellular Biochemistry

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Human transmembrane serine protease 2 (TMPRSS2) is an important member of the type 2 transmembrane serine protease (TTSP) family with significant therapeutic markings. The search for potent TMPRSS2 inhibitors against severe acute respiratory syndrome coronavirus 2 infection with favorable tissue specificity and off‐site toxicity profiles remains limited. Therefore, probing the anti‐TMPRSS2 potential of enhanced drug delivery systems, such as nanotechnology and prodrug systems, has become compelling. We report the first in silico study of TMPRSS2 against a prodrug, [isopropyl(S)‐2‐((S)‐2‐acetamido‐3‐(1H‐indol‐3‐yl)‐propanamido)‐6‐diazo‐5‐oxo‐hexanoate] also known as DRP‐104 synthesized from 6‐Diazo‐5‐oxo‐l‐norleucine (DON). We performed comparative studies on DON and DRP‐104 against a clinically potent TMPRSS2 inhibitor, nafamostat, and a standard serine protease inhibitor, 4‐(2‐Aminoethyl) benzenesulfonyl fluoride (AEBSF) against TMPRSS2 and found improved TMPRSS2 inhibition through synergistic binding of the S1/S1' subdomains. Both DON and DRP‐104 had better thermodynamic profiles than AEBSF and nafamostat. DON was found to confer structural stability with strong positive correlated inter‐residue motions, whereas DRP‐104 was found to confer kinetic stability with restricted residue displacements and reduced loop flexibility. Interestingly, the Scavenger Receptor Cysteine‐Rich (SRCR) domain of TMPRSS2 may be involved in its inhibition mechanics. Two previously unidentified loops, designated X (270−275) and Y (293−296) underwent minimal and major structural transitions, respectively. In addition, residues 273−277 consistently transitioned to a turn conformation in all ligated systems, whereas unique transitions were identified for other transitioning residue groups in each TMPRSS2‐inhibitor complex. Intriguingly, while both DON and DRP‐104 showed similar loop transition patterns, DRP‐104 preserved loop structural integrity. As evident from our systematic comparative study using experimentally/clinically validated inhibitors, DRP‐104 may serve as a potent and novel TMPRSS2 inhibitor and warrants further clinical investigation.

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Harnessing proteases for T regulatory cell immunotherapy

Cited by 4 publications

References 83 publications

CD4+ T-Cell Legumain Deficiency Attenuates Hypertensive Damage via Preservation of TRAF6

CD4+ T-Cell Legumain Deficiency Attenuates Hypertensive Damage via Preservation of TRAF6

Transcriptional and posttranslational regulation of Th17/Treg balance in health and disease

DON/DRP‐104 as potent serine protease inhibitors implicated in SARS‐CoV‐2 infection: Comparative binding modes with human TMPRSS2 and novel therapeutic approach

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