Immune checkpoint molecule TIGIT manipulates T cell dysfunction in septic patients

Sun, Yujing; Ding, Renyu; Chang, Yu-Hsin; Li, Jiuming; Ma, Xiaochun

doi:10.1016/j.intimp.2021.108205

Cited by 6 publications

(4 citation statements)

References 38 publications

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“…Following CLP, the expression of TIGIT and CD155 in liver, lung and kidney tissues were increased. Further analysis showed that there was a significantly increased TIGIT expression on both T cells and NK cells 24 hours after CLP challenge, in accordance with published study ( 34 ) that TIGIT expression on T cells was upregulated in septic patients. CD155 is expressed on monocytes, dendritic cells and a variety of nonhematopoietic cell types ( 15 ).…”

Section: Discussionsupporting

confidence: 91%

TIGIT regulates CD4+ T cell immunity against polymicrobial sepsis

Zhong,

Xie,

Wang

et al. 2024

Front. Immunol.

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BackgroundSepsis is one of the major causes of death and increased health care burden in modern intensive care units. Immune checkpoints have been prompted to be key modulators of T cell activation, T cell tolerance and T cell exhaustion. This study was designed to investigate the role of the negative immune checkpoint, T cell immunoglobulin and ITIM domain (TIGIT), in the early stage of sepsis.MethodAn experimental murine model of sepsis was developed by cecal ligation and puncture (CLP). TIGIT and CD155 expression in splenocytes at different time points were assessed using flow cytometry. And the phenotypes of TIGIT-deficient (TIGIT-/-) and wild-type (WT) mice were evaluated to explore the engagement of TIGIT in the acute phase of sepsis. In addition, the characteristics were also evaluated in the WT septic mice pretreated with anti-TIGIT antibody. TIGIT and CD155 expression in tissues was measured using real-time quantitative PCR and immunofluorescence staining. Proliferation and effector function of splenic immune cells were evaluated by flow cytometry. Clinical severity and tissue injury were scored to evaluate the function of TIGIT on sepsis. Additionally, tissue injury biomarkers in peripheral blood, as well as bacterial load in peritoneal lavage fluid and liver were also measured.ResultsThe expression of TIGIT in splenic T cells and NK cells was significantly elevated at 24 hours post CLP.TIGIT and CD155 mRNA levels were upregulated in sepsis-involved organs when mice were challenged with CLP. In CLP-induced sepsis, CD4+ T cells from TIGIT-/- mice shown increased proliferation potency and cytokine production when compared with that from WT mice. Meanwhile, innate immune system was mobilized in TIGIT-/- mice as indicated by increased proportion of neutrophils and macrophages with potent effector function. In addition, tissue injury and bacteria burden in the peritoneal cavity and liver was reduced in TIGIT-/- mice with CLP induced sepsis. Similar results were observed in mice treated with anti-TIGIT antibody.ConclusionTIGIT modulates CD4+ T cell response against polymicrobial sepsis, suggesting that TIGIT could serve as a potential therapeutic target for sepsis.

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Section: Discussionsupporting

confidence: 91%

TIGIT regulates CD4+ T cell immunity against polymicrobial sepsis

Zhong,

Xie,

Wang

et al. 2024

Front. Immunol.

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“…The limitations of the present study concern the need for more data involving the measurement of the TIGIT + Tregs during ICU stay and the follow-up of the patients to determine the burden of the secondary infection and its correlation with TIGIT. However, supported by previous reports that TIGIT blockade can restore the effector functions of TCD8 + cells during experimental sepsis 38 and experimental model of chronic viral infection by LCMV 39 , we suggest that therapies aiming the TIGIT blockade would be beneficial in preventing nosocomial and opportunistic infections in hospitalized COVID-19 patients.…”

Section: Discussionsupporting

confidence: 84%

The TIGIT+ T regulatory cells subset associates with nosocomial infection and fatal outcome in COVID-19 patients under mechanical ventilation

de Lima,

Machado,

Nascimento

et al. 2023

Sci Rep

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The TIGIT+FOXP3+Treg subset (TIGIT+Tregs) exerts robust suppressive activity on cellular immunity and predisposes septic individuals to opportunistic infection. We hypothesized that TIGIT+Tregs could play an important role in intensifying the COVID-19 severity and hampering the defense against nosocomial infections during hospitalization. Herein we aimed to verify the association between the levels of the TIGIT+Tregs with the mechanical ventilation requirement, fatal outcome, and bacteremia during hospitalization. TIGIT+Tregs were immunophenotyped by flow cytometry from the peripheral blood of 72 unvaccinated hospitalized COVID-19 patients at admission from May 29th to August 6th, 2020. The patients were stratified during hospitalization according to their mechanical ventilation requirement and fatal outcome. COVID-19 resulted in a high prevalence of the TIGIT+Tregs at admission, which progressively increased in patients with mechanical ventilation needs and fatal outcomes. The prevalence of TIGIT+Tregs positively correlated with poor pulmonary function and higher plasma levels of LDH, HMGB1, FGL2, and TNF. The non-survivors presented higher plasma levels of IL-33, HMGB1, FGL2, IL-10, IL-6, and 5.54 times more bacteremia than survivors. Conclusions: The expansion of the TIGIT+Tregs in COVID-19 patients was associated with inflammation, lung dysfunction, bacteremia, and fatal outcome.

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“…Inspection of transcripts that contribute to the CoGAPS gene expression phenotypes include those previously linked to immunosuppression and sepsis outcomes. Genes high in the CD8 + T-cell\NK-cell pattern 12 include GZMH (CTLA1), GZMK and TIGIT 31,36 and IL7R in the CD4 + T-cell pattern 27 8 (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

Gene expression signatures in blood from a West African sepsis cohort define host response phenotypes

Chenoweth,

Colantuoni,

Striegel

et al. 2024

Nat Commun

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Our limited understanding of the pathophysiological mechanisms that operate during sepsis is an obstacle to rational treatment and clinical trial design. There is a critical lack of data from low- and middle-income countries where the sepsis burden is increased which inhibits generalized strategies for therapeutic intervention. Here we perform RNA sequencing of whole blood to investigate longitudinal host response to sepsis in a Ghanaian cohort. Data dimensional reduction reveals dynamic gene expression patterns that describe cell type-specific molecular phenotypes including a dysregulated myeloid compartment shared between sepsis and COVID-19. The gene expression signatures reported here define a landscape of host response to sepsis that supports interventions via targeting immunophenotypes to improve outcomes.

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Immune checkpoint molecule TIGIT manipulates T cell dysfunction in septic patients

Cited by 6 publications

References 38 publications

TIGIT regulates CD4+ T cell immunity against polymicrobial sepsis

TIGIT regulates CD4+ T cell immunity against polymicrobial sepsis

The TIGIT+ T regulatory cells subset associates with nosocomial infection and fatal outcome in COVID-19 patients under mechanical ventilation

Gene expression signatures in blood from a West African sepsis cohort define host response phenotypes

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