Sepsis-Induced Immunosuppression Is Marked by an Expansion of a Highly Suppressive Repertoire of FOXP3+ T-Regulatory Cells Expressing TIGIT

Lima, Mikhael Haruo Fernandes de; Hiroki, Carlos Hiroji; Borges, Vanessa de Fátima; Cebinelli, Guilherme Cesar Martelossi; Santos, Jandir C.; Rosa, Marcos Henrique; Silva, Camilla Meireles S; Wanderley, Carlos W.; Gonçalves, Augusto Velozo; Quirino, Gustavo F. S.; Zamboni, Dario S.; Cunha, Thiago Mattar; Filho, José-Carlos A.; Cunha, Fernando Q.

doi:10.1093/infdis/jiab405

Cited by 12 publications

(11 citation statements)

References 25 publications

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“…TIGIT expression in prior studies was associated with both an increased immunosuppressive potential of Tregs and an activated and proinflammatory transcriptional profile of TIGITexpressing Tregs. 6,42 Our data demonstrating a pathogenic role for TIGIT in experimental AKI is supported by other studies that found a correlation between TIGIT expression and non-AKI disease severity. Elevated TIGIT on T cells positively correlated with markers of autoimmunity and inflammation in patients with rheumatoid arthritis and systemic lupus erythematosus disease activity index.…”

Section: Discussionsupporting

confidence: 85%

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Immune Checkpoint Molecule TIGIT Regulates Kidney T Cell Functions and Contributes to AKI

Noel

Lee

Gharaie

et al. 2023

JASN

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Significance Statement T cells mediate pathogenic and reparative processes during AKI, but the exact mechanisms regulating kidney T cell functions are unclear. This study identified upregulation of the novel immune checkpoint molecule, TIGIT, on mouse and human kidney T cells after AKI. TIGIT-expressing kidney T cells produced proinflammatory cytokines and had effector (EM) and central memory (CM) phenotypes. TIGIT-deficient mice had protection from both ischemic and nephrotoxic AKI. Single-cell RNA sequencing led to the discovery of possible downstream targets of TIGIT. TIGIT mediates AKI pathophysiology, is a promising novel target for AKI therapy, and is being increasingly studied in human cancer therapy trials. Background T cells play pathogenic and reparative roles during AKI. However, mechanisms regulating T cell responses are relatively unknown. We investigated the roles of the novel immune checkpoint molecule T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) in kidney T cells and AKI outcomes. Methods TIGIT expression and functional effects were evaluated in mouse kidney T cells using RNA sequencing (RNA-Seq) and flow cytometry. TIGIT effect on AKI outcomes was studied with TIGIT knockout (TIGIT-KO) mice in ischemia reperfusion (IR) and cisplatin AKI models. Human kidney T cells from nephrectomy samples and single cell RNA sequencing (scRNA-Seq) data from the Kidney Precision Medicine Project were used to assess TIGIT's role in humans. Results RNA-Seq and flow cytometry analysis of mouse kidney CD4+ T cells revealed increased expression of TIGIT after IR injury. Ischemic injury also increased TIGIT expression in human kidney T cells, and TIGIT expression was restricted to T/natural killer cell subsets in patients with AKI. TIGIT-expressing kidney T cells in wild type (WT) mice had an effector/central memory phenotype and proinflammatory profile at baseline and post-IR. Kidney regulatory T cells were predominantly TIGIT+ and significantly reduced post-IR. TIGIT-KO mice had significantly reduced kidney injury after IR and nephrotoxic injury compared with WT mice. scRNA-Seq analysis showed enrichment of genes related to oxidative phosphorylation and mTORC1 signaling in Th17 cells from TIGIT-KO mice. Conclusions TIGIT expression increases in mouse and human kidney T cells during AKI, worsens AKI outcomes, and is a novel therapeutic target for AKI.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Immune Checkpoint Molecule TIGIT Regulates Kidney T Cell Functions and Contributes to AKI

Noel

Lee

Gharaie

et al. 2023

JASN

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“…Some other studies have shown that augmentation of TIGIT + Treg was associated with a high expression of Helios and Nrp-1 when the body exerted its immunosuppressive function. 21,22 By giving TIGIT-Fc treatment, we found that the expressions of Helios and Foxp3 were increased, whereas Nrp-1 was not. This indicates that TIGIT-Fc treatment improved the immune status of allogeneic transplantation in mice FIGURE 3.…”

Section: Discussionmentioning

confidence: 86%

TIGIT-Fc Prolongs Corneal Allograft Survival in Mice by Upregulating TIGIT/CD226 Expression and the Proportion of Helios+Foxp3+ Treg Cells

Zhang

et al. 2023

Transplantation

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Background. Reduction of graft rejection remains key issue for supporting long-term graft retention after corneal transplantation. The relevance of Treg in reduction of corneal allografts rejection has been demonstrated. It has been recently reported that in addition to Foxp3, Helios is also considered to be a marker of activated Treg. Helios+Foxp3+ Treg are considered to be the true immunosuppressive Treg. TIGIT is an immunosuppressive costimulatory molecule that was found to be highly expressed on the surface of Helios+Foxp3+ Treg. Methods. In this study, we aimed to explore whether supplementing TIGIT would result in an expansion and activation of Helios+Foxp3+ Treg thus to mediate an immune tolerance following corneal transplantation by administering topically and systemically TIGIT-Fc treatment in murine models. Results. TIGIT-Fc treatment significantly improved the survival of corneal allograft compared with the control group. TIGIT-Fc treatment increased TIGIT/CD226 expression, the proportion of Helios+Foxp3+ Treg cells and an enhanced ex vivo suppressive effect from peripheral lymph nodes isolated Treg cells. Furthermore, the expression of Helios in corneal grafts was upregulated, whereas expression of CD226 and production of aqueous interferon-γ and VEGF were reduced by TIGIT-Fc treatment. Conclusions. TIGIT-Fc treatment could specifically upregulate Helios+Foxp3+ Treg-mediated immune response after allogeneic corneal transplantation via TIGIT/CD226-CD155 pathway which improves the survival of allografts.

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“…IL-33 can selectively amplify ST2 + Tregs. ST2 + Tregs promote IL-13 and TGF-β release to inhibit inflammation and CD4 + T cell proliferation ( 31 , 32 ). Enhanced IL-10 production in macrophages promotes macrophage polarization to the M2 anti-inflammatory phenotype, which suppresses foam cell production ( 25 ) ( Figure 4 ).…”

Section: Systematic Reviewmentioning

confidence: 99%

IL-33/ST2 immunobiology in coronary artery disease: A systematic review and meta-analysis

Liu

Liu²,

Wei³

et al. 2022

Front. Cardiovasc. Med.

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The IL-33/ST2 axis is reported to be controversially associated with coronary artery disease (CAD). A systematic review of the association between the IL-33/ST2 axis and CAD revealed that IL-33/ST2 plays a protective role in CAD and serum sST2 and IL-33 levels are increased in patients with cardiovascular disease. Therefore, the association of IL-33/ST2 single nucleotide polymorphisms (SNPs) with CAD prevalence, prognosis, and risk factors was assessed by performing a meta-analysis. Through a literature search of relevant articles in various databases using the relevant keywords, seven studies were included in the analysis. The meta-analysis showed that the IL-33/ST2 axis was associated with increased CAD risk [pooled odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.13–1.20]. Gene subgroup analysis showed a close association of IL1RL1 (OR = 1.25, 95% CI: 1.20–1.30; I2 = 85.9%; p = 0.000) and IL1RAcP (OR = 1.42, 95% CI: 1.26–1.60; I2 = 27.1%; p = 0.203) with increased CAD risk. However, the association for the IL-33 gene was not statistically significant. SNPs rs7044343 (T), rs10435816 (G), rs11792633 (C) in IL-33 gene were associated with a protective effect in CAD. However, rs7025417 (T) in IL-33, rs11685424 (G) in IL1RL1, rs950880 (A) in sST2, and rs4624606 (A) in IL1RAcP were related to increased CAD risk. Overall, polymorphisms in IL-33/ST2 axis components were associated with increased CAD risk. These results may help identify key features of IL-33/ST2 immunobiology in CAD along with potential treatment strategies to lower disease burden.

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Sepsis-Induced Immunosuppression Is Marked by an Expansion of a Highly Suppressive Repertoire of FOXP3+ T-Regulatory Cells Expressing TIGIT

Cited by 12 publications

References 25 publications

Immune Checkpoint Molecule TIGIT Regulates Kidney T Cell Functions and Contributes to AKI

Immune Checkpoint Molecule TIGIT Regulates Kidney T Cell Functions and Contributes to AKI

TIGIT-Fc Prolongs Corneal Allograft Survival in Mice by Upregulating TIGIT/CD226 Expression and the Proportion of Helios+Foxp3+ Treg Cells

IL-33/ST2 immunobiology in coronary artery disease: A systematic review and meta-analysis

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