Btla signaling in conventional and regulatory lymphocytes coordinately tempers humoral immunity in the intestinal mucosa

Stienne, Caroline; Virgen-Slane, Richard; Elmén, Lisa; Veny, Marisol; Huang, Sarah X.L.; Nguyen, Jennifer; Chappell, Elizabeth; Balmert, M. Olivia; Shui, Jr-Wen; Hurchla, Michelle A.; Kronenberg, Mitchell; Peterson, Scott N.; Murphy, Kenneth M.; Ware, Carl F.; Šedý, John

doi:10.1016/j.celrep.2022.110553

Cited by 10 publications

(7 citation statements)

References 82 publications

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“…This finding extends on recently published in vitro data, showing a negative correlation of BTLA signaling and transcription of an INFγ response gene set. 25 Mechanistically, we demonstrate that BTLA-deficient T effector cells evade Treg-mediated suppression in vitro , a finding consistent with previous observations by others. 35 By contrast, Btla KO Tregs retained their suppressive capacity in vitro and in vivo , exhibited similar survival, and did not show impaired renal trafficking.…”

Section: Discussionsupporting

confidence: 92%

“…Although early work did not show any effect of BTLA deletion on Tregs, recently, BTLA signaling was shown to activate transcription factors associated with Treg differentiation in vitro . 25 By contrast, Albring et al demonstrated a proliferative effect through BTLA activation on Tregs rather than de novo differentiation in vivo . 35 Adding to the complexity, BTLA + DCs were shown to induce pTregs in a model of EAE.…”

Section: Discussionmentioning

confidence: 96%

“…However, given the complex expression pattern of BTLA, cell-type-specific deletion may reveal the full complexity of this signaling pathway in the kidney. 25 To this end, future studies will have to address the differential effect on T-cell subsets and B cells in different glomerular inflammation models in more detail.…”

Section: Discussionmentioning

confidence: 99%

“…This is in contrast to reported functions in the liver, where BTLA deficiency led to spontaneous autoimmune hepatitis. 18 In addition, Stienne et al 25 showed a dysregulation of B cells and T follicular helper cells leading to increased IgA production in the gut of older mice carrying a specific Btla KO in B cells or CD4 + T cells. Of note, both studies did not report a renal phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, as a selective deletion of Btla on Foxp3 1 Tregs resulted in a decrease in Treg numbers, a cell-intrinsic supportive function of BTLA in Tregs was postulated. 25 Overexpression of BTLA was recently described to be beneficial in a murine model of kidney transplant rejection. 26,27 The same study showed a reduced BTLA expression in T cells of patients with acute kidney transplant rejection, suggesting a role in human disease.…”

Section: Introductionmentioning

confidence: 99%

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Stimulation of Immune Checkpoint Molecule B and T-Lymphocyte Attenuator Alleviates Experimental Crescentic Glomerulonephritis

Diefenhardt,

Braumann,

Schömig

et al. 2023

JASN

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Background Modulating T-lymphocytes represents a promising targeted therapeutic option for glomerulonephritis (GN) because these cells mediate damage in various experimental and human GN types. The immune checkpoint molecule B and T-lymphocyte attenuator (BTLA) has shown its potential to restrain inflammation in other T-cell–mediated disease models. Its role in GN, however, has not been investigated. Methods We induced nephrotoxic nephritis (NTN), a mouse model of crescentic GN, in Btla-deficient (Btla KO) mice and wild-type littermate controls and assessed disease severity using functional and histologic parameters at different time points after disease induction. Immunologic changes were comprehensively evaluated by flow cytometry, RNA sequencing, and in vitro assays for dendritic cell and T-cell function. Transfer experiments into Rag1 KO mice confirmed the observed in vitro findings. In addition, we evaluated the potential of an agonistic anti-BTLA antibody to treat NTN in vivo. Results The Btla KO mice developed aggravated NTN, driven by an increase of infiltrating renal Th1 cells. Single-cell RNA sequencing showed increased renal T-cell activation and positive regulation of the immune response. Although BTLA-deficient regulatory T cells (Tregs) exhibited preserved suppressive function in vitro and in vivo, Btla KO T effector cells evaded Treg suppression. Administration of an agonistic anti-BTLA antibody robustly attenuated NTN by suppressing nephritogenic T effector cells and promoting Treg expansion. Conclusions In a model of crescentic GN, BTLA signaling effectively restrained nephritogenic Th1 cells and promoted regulatory T cells. Suppression of T-cell–mediated inflammation by BTLA stimulation may prove relevant for a broad range of conditions involving acute GN.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stimulation of Immune Checkpoint Molecule B and T-Lymphocyte Attenuator Alleviates Experimental Crescentic Glomerulonephritis

Diefenhardt,

Braumann,

Schömig

et al. 2023

JASN

View full text Add to dashboard Cite

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Mulberry Leaf Lipid Nanoparticles: a Naturally Targeted CRISPR/Cas9 Oral Delivery Platform for Alleviation of Colon Diseases

Ma,

Gao

et al. 2024

Small

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Oral treatment of colon diseases with the CRISPR/Cas9 system has been hampered by the lack of a safe and efficient delivery platform. Overexpressed CD98 plays a crucial role in the progression of ulcerative colitis (UC) and colitis‐associated colorectal cancer (CAC). In this study, lipid nanoparticles (LNPs) derived from mulberry leaves are functionalized with Pluronic copolymers and optimized to deliver the CRISPR/Cas gene editing machinery for CD98 knockdown. The obtained LNPs possessed a hydrodynamic diameter of 267.2 nm, a narrow size distribution, and a negative surface charge (−25.6 mV). Incorporating Pluronic F127 into LNPs improved their stability in the gastrointestinal tract and facilitated their penetration through the colonic mucus barrier. The galactose end groups promoted endocytosis of the LNPs by macrophages via asialoglycoprotein receptor‐mediated endocytosis, with a transfection efficiency of 2.2‐fold higher than Lipofectamine 6000. The LNPs significantly decreased CD98 expression, down‐regulated pro‐inflammatory cytokines (TNF‐α and IL‐6), up‐regulated anti‐inflammatory factors (IL‐10), and polarized macrophages to M2 phenotype. Oral administration of LNPs mitigated UC and CAC by alleviating inflammation, restoring the colonic barrier, and modulating intestinal microbiota. As the first oral CRISPR/Cas9 delivery LNP, this system offers a precise and efficient platform for the oral treatment of colon diseases.

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BTLA and HVEM: Emerging players in the tumor microenvironment and cancer progression

Mohamed,

Obeid,

Fadhil

et al. 2023

Cytokine

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Btla signaling in conventional and regulatory lymphocytes coordinately tempers humoral immunity in the intestinal mucosa

Cited by 10 publications

References 82 publications

Stimulation of Immune Checkpoint Molecule B and T-Lymphocyte Attenuator Alleviates Experimental Crescentic Glomerulonephritis

Stimulation of Immune Checkpoint Molecule B and T-Lymphocyte Attenuator Alleviates Experimental Crescentic Glomerulonephritis

Mulberry Leaf Lipid Nanoparticles: a Naturally Targeted CRISPR/Cas9 Oral Delivery Platform for Alleviation of Colon Diseases

BTLA and HVEM: Emerging players in the tumor microenvironment and cancer progression

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