Hobit- and Blimp-1-driven CD4+ tissue-resident memory T cells control chronic intestinal inflammation

Introduction/AbstractT lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro-inflammatory cytokines upon re-stimulation in vitro1–29. Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA)30–33. However, the functions of T lymphocytes in established disease remain elusive. Here we dissect the heterogeneity of synovial T lymphocytes in JIA patients by single cell RNA-sequencing. We identify subpopulations of T lymphocytes expressing genes reflecting recent activation by antigen in situ. A PD-1+TOX+EOMES+ population of CD4+ T lymphocytes expressed immune regulatory genes and chemoattractant genes for myeloid cells. A PD-1+TOX+BHLHE40+ population of CD4+, and a mirror population of CD8+ T lymphocytes expressed genes driving inflammation, and genes supporting B lymphocyte activation. This analysis points out that multiple types of T lymphocytes have to be targeted for therapeutic regeneration of tolerance in arthritis.

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“…1e; Extended Data Fig. 3) 52–55 . Cells of cluster 4 represented 4.1% (2.5%-6.2%) of synovial Tcon (Fig.…”

Section: Main Textmentioning

confidence: 99%

Antigen-driven PD-1⁺TOX⁺EOMES⁺and PD-1⁺TOX⁺BHLHE40⁺synovial T lymphocytes regulate chronic inflammationin situ

Maschmeyer

Heinz

Skopnik

et al. 2019

Preprint

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“…Furthermore, in CD, αEβ7 is highly expressed on the expanded subset of CD4 + T lymphocytes expressing the activating receptor NKG2D, which exhibits pro‐inflammatory and cytotoxic properties . Recently, it was also demonstrated that the extent of CD4 + CD69 + αE + tissue‐resident T mem (TRM) cells is predictive of the development of flares in patients with IBD, and CD4 TRM cells in CD are a major source of mucosal TNF‐α …”

Section: Immune Cell Functions In the Gut And Ibdmentioning

confidence: 99%

“…Completed phase 1 and 2 and ongoing phase 3 clinical trials have shown that blockade of αEβ7 with etrolizumab is well tolerated, with rates of serious adverse events similar to those with placebo . In addition, both CD4 + αEβ7 + and CD8 + αEβ7 + cells are pro‐inflammatory in phenotype; CD4 + αEβ7 + demonstrating fewer markers associated with T reg cells including FoxP3 relative to CD4 + αEβ7 − lymphocytes …”

Section: Safety Of Anti‐integrin Therapiesmentioning

confidence: 99%

“…73 Furthermore, in CD, αEβ7 is highly expressed on the expanded subset of CD4 + T lymphocytes expressing the activating receptor NKG2D, which exhibits pro-inflammatory and cytotoxic properties. 81 Recently, it was also demonstrated that the extent of CD4 + CD69 + αE + tissue-resident T mem (TRM) cells is predictive of the development of flares in patients with IBD, 82 and CD4 TRM cells in CD are a major source of mucosal TNF-α. 83 The frequency of αEβ7 + -bearing T lymphocytes is generally higher in the ileum relative to the colon-this, coupled with a dysregulated function of these cells, may exacerbate the widespread inflammation associated with CD.…”

Section: αEβ7-expressing T Lymphocytesmentioning

confidence: 99%

“…CD4 + αEβ7 + demonstrating fewer markers associated with T reg cells including FoxP3 relative to CD4 + αEβ7 − lymphocytes. 73,82,143 6 | CONCLUSIONS AND FUTURE DIRECTIONS Evidence suggests that integrins are critical players in IBD pathogenesis, and recent clinical data have begun to elucidate the therapeutic benefit of anti-integrin blockade in IBD. Anti-integrin therapies with gut selectivity offer a new class of therapeutics that are safe and well tolerated and hold significant promise for efficacy in both UC and CD.…”

Section: Safety Of Anti-integrin Therapiesmentioning

confidence: 99%

See 2 more Smart Citations

The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies

Dotan

Allez

Danese

et al. 2019

Medicinal Research Reviews

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Inflammatory bowel disease (IBD) is characterized by uncontrolled inflammation in the gastrointestinal tract. The underlying pathobiology of IBD includes an increase in infiltrating gut‐homing lymphocytes. Although lymphocyte homing is typically a tightly regulated and stepwise process involving multiple integrins and adhesion molecules expressed on endothelial cells, the distinct roles of integrin‐expressing immune cells is not fully understood in the pathology of IBD. In this review, we detail the involvement of integrins expressed on specific lymphocyte subsets in the pathogenesis of IBD and discuss the current status of approved and investigational integrin‐targeted therapies.

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Mitochondrial Control of Proteasomal Psmb5 Drives the Differentiation of Tissue‐Resident Memory T Cells in Patients with Rheumatoid Arthritis

Wu,

Su,

Zhang

et al. 2024

Arthritis & Rheumatology

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ObjectiveTo explore T‐cell‐intrinsic mechanisms underpinning the mal‐differentiation of tissue‐resident memory T (Trm) cells in patients with rheumatoid arthritis (RA).MethodsCirculating T cells from RA patients and healthy individuals were used for Trm cell differentiation. The role of Hobit in Trm differentiation was investigated through targeted silencing experiments. Psmb5 expression regulation was explored by identifying BRD2 as a key transcription factor, with the interaction validated through ChIP‐qPCR. The impact of BRD2 succinylation on Trm differentiation was examined by manipulating succinyl‐CoA levels in T cells. Humanized NSG chimeras representing synovitis provided insights into Trm infiltration in RA synovitis and were utilized for translational experiments.ResultsIn RA patients, a notable predisposition of CD4+ T cells towards differentiation into Trm cells was observed, demonstrating a positive correlation with the Disease Activity Score 28. Remarkably, Hobit was a pivotal facilitator in the formation of RA CD4+ Trm cells. Mechanistic studies unveiled the dysregulation of proteasomal Psmb5 in T cells of RA patients as the key factor contributing to elevated Hobit protein levels. The deficiency of proteasomal Psmb5 was intricately linked to BRD2, with succinylation exerting a significant impact on Psmb5 transcription and Trm cell differentiation. This heightened BRD2 succinylation was attributed to elevated levels of mitochondrial succinyl‐CoA in RA T cells. Consequently, targeting succinyl‐CoA within CD4+ T cells controlled the inflammation of synovial tissues in humanized chimeras.ConclusionMitochondrial succinyl‐CoA fosters the succinylation of BRD2, resulting in compromised transcription of proteasomal Psmb5 and the differentiation of Trm cells in RA.

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Hobit- and Blimp-1-driven CD4+ tissue-resident memory T cells control chronic intestinal inflammation

Cited by 180 publications

References 53 publications

Antigen-driven PD-1⁺TOX⁺EOMES⁺and PD-1⁺TOX⁺BHLHE40⁺synovial T lymphocytes regulate chronic inflammationin situ

Antigen-driven PD-1⁺TOX⁺EOMES⁺and PD-1⁺TOX⁺BHLHE40⁺synovial T lymphocytes regulate chronic inflammationin situ

The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies

Mitochondrial Control of Proteasomal Psmb5 Drives the Differentiation of Tissue‐Resident Memory T Cells in Patients with Rheumatoid Arthritis

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Hobit- and Blimp-1-driven CD4+ tissue-resident memory T cells control chronic intestinal inflammation

Cited by 180 publications

References 53 publications

Antigen-driven PD-1+TOX+EOMES+and PD-1+TOX+BHLHE40+synovial T lymphocytes regulate chronic inflammationin situ

Antigen-driven PD-1+TOX+EOMES+and PD-1+TOX+BHLHE40+synovial T lymphocytes regulate chronic inflammationin situ

The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies

Mitochondrial Control of Proteasomal Psmb5 Drives the Differentiation of Tissue‐Resident Memory T Cells in Patients with Rheumatoid Arthritis

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Product

Resources

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Antigen-driven PD-1⁺TOX⁺EOMES⁺and PD-1⁺TOX⁺BHLHE40⁺synovial T lymphocytes regulate chronic inflammationin situ

Antigen-driven PD-1⁺TOX⁺EOMES⁺and PD-1⁺TOX⁺BHLHE40⁺synovial T lymphocytes regulate chronic inflammationin situ