CD3+CD4–CD8– Double-negative αβ T cells attenuate lung ischemia-reperfusion injury

Bortezomib is a well-established treatment option for patients with multiple myeloma (MM). It is a selective and reversible inhibitor of the proteasome that is responsible for the degradation of many regulatory proteins that are involved in apoptosis, cell-cycle regulation, or transcription. Because patients with MM are prone to develop acute renal failure, we evaluated the influence of Bortezomib on renal ischemia-reperfusion injury (IRI). Mice were subjected to renal IRI by having the renal pedicles clamped for 30 min followed by reperfusion for 3, 24, and 48 h. Mice were either pretreated with 0.5 mg/kg body wt Bortezomib or vehicle intravenously 12 h before induction of IRI. Serum creatinine and tubular necrosis were significantly increased in Bortezomib compared with vehicle-treated mice. The inflammatory response was found to be significantly decreased in Bortezomib-treated mice as reflected by a decreased infiltration of CD4+ T cells and a significantly decreased Th1 cytokine expression in the kidneys. In contrast, apoptosis was significantly increased in kidneys of Bortezomib-treated mice compared with vehicle-treated controls. Increased numbers of TUNEL-positive cells/mm2 and increased mRNA expression of proapoptotic factors were detected in kidneys of Bortezomib-treated mice. Of note, p21, a cell senescence marker, was also significantly increased in kidneys of Bortezomib-treated mice. In summary, we provide evidence that Bortezomib worsens the outcome of renal IRI by leading to increased apoptosis of tubular cells despite decreased infiltrating T cells and proinflammatory mediators.

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Liver grafts from CD39-overexpressing rodents are protected from ischemia reperfusion injury due to reduced numbers of resident CD4+T cells

Hepatology ◽

10.1002/hep.25985 ◽

2013 ◽

Vol 57 (4) ◽

pp. 1597-1606 ◽

Cited By ~ 31

Author(s):

Sandra Pommey ◽

Bo Lu ◽

Jennifer McRae ◽

John Stagg ◽

Prue Hill ◽

...

Keyword(s):

T Cells ◽

Reperfusion Injury ◽

Cd4 T Cells ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion

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Role of α/β and γ/δ T cells in renal ischemia-reperfusion injury

AJP Renal Physiology ◽

10.1152/ajprenal.00486.2006 ◽

2007 ◽

Vol 293 (3) ◽

pp. F741-F747 ◽

Cited By ~ 31

Author(s):

Kathrin Hochegger ◽

Tobias Schätz ◽

Philipp Eller ◽

Andrea Tagwerker ◽

Dorothea Heininger ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Wild Type ◽

Renal Ischemia Reperfusion Injury ◽

Deficient Mice

T cells have been implicated in the pathogenesis of renal ischemia-reperfusion injury (IRI). To date existing data about the role of the T cell receptor (Tcr) are contradictory. We hypothesize that the Tcr plays a prominent role in the late phase of renal IRI. Therefore, renal IRI was induced in α/β, γ/δ T cell-deficient and wild-type mice by clamping renal pedicles for 30 min and reperfusing for 24, 48, 72, and 120 h. Serum creatinine increased equally in all three groups 24 h after ischemia but significantly improved in Tcr-deficient animals compared with wild-type controls after 72 h. A significant reduction in renal tubular injury and infiltration of CD4+ T-cells in both Tcr-deficient mice compared with wild-type controls was detected. Infiltration of α/β T cells into the kidney was reduced in γ/δ T cell-deficient mice until 72 h after ischemia. In contrast, γ/δ T cell infiltration was equal in wild-type and α/β T cell-deficient mice, suggesting an interaction between α/β and γ/δ T cells. Data from γ/δ T cell-deficient mice were confirmed by in vivo depletion of γ/δ T cells in C57BL/6 mice. Whereas α/β T cell-deficient mice were still protected after 120 h, γ/δ T cell-deficient mice showed a “delayed wild-type phenotype” with a dramatic increase in kidney-infiltrating α/β, Tcr-expressing CD4+ T-cells. This report provides further evidence that α/β T cells are major effector cells in renal IRI, whereas γ/δ T cells play a role as mediator cells in the first 72 h of renal IRI.

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Ag-specific CD4 T cells promote innate immune responses in liver ischemia reperfusion injury

Cellular and Molecular Immunology ◽

10.1038/s41423-018-0051-x ◽

2018 ◽

Vol 16 (1) ◽

pp. 98-100 ◽

Cited By ~ 3

Author(s):

Jianhua Rao ◽

Feng Cheng ◽

Shikun Yang ◽

Yuan Zhai ◽

Ling Lu

Keyword(s):

T Cells ◽

Immune Responses ◽

Reperfusion Injury ◽

Cd4 T Cells ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Innate Immune ◽

Liver Ischemia ◽

Innate Immune Responses

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A Unique Population of Regulatory T Cells in Heart Potentiates Cardiac Protection From Myocardial Infarction

Circulation ◽

10.1161/circulationaha.120.046789 ◽

2020 ◽

Vol 142 (20) ◽

pp. 1956-1973

Author(s):

Ni Xia ◽

Yuzhi Lu ◽

Muyang Gu ◽

Nana Li ◽

Meilin Liu ◽

...

Keyword(s):

Myocardial Infarction ◽

T Cells ◽

T Cell ◽

Reperfusion Injury ◽

T Cell Receptor ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Cell Receptor ◽

Interleukin 33 ◽

Injured Myocardium

Background: Regulatory T cells (Tregs), traditionally recognized as potent suppressors of immune response, are increasingly attracting attention because of a second major function: residing in parenchymal tissues and maintaining local homeostasis. However, the existence, unique phenotype, and function of so-called tissue Tregs in the heart remain unclear. Methods: In mouse models of myocardial infarction (MI), myocardial ischemia/reperfusion injury, or cardiac cryoinjury, the dynamic accumulation of Tregs in the injured myocardium was monitored. The bulk RNA sequencing was performed to analyze the transcriptomic characteristics of Tregs from the injured myocardium after MI or ischemia/reperfusion injury. Photoconversion, parabiosis, single-cell T-cell receptor sequencing, and adoptive transfer were applied to determine the source of heart Tregs. The involvement of the interleukin-33/suppression of tumorigenicity 2 axis and Sparc (secreted acidic cysteine-rich glycoprotein), a molecule upregulated in heart Tregs, was further evaluated in functional assays. Results: We showed that Tregs were highly enriched in the myocardium of MI, ischemia/reperfusion injury, and cryoinjury mice. Transcriptomic data revealed that Tregs isolated from the injured hearts had plenty of differentially expressed transcripts in comparison with their lymphoid counterparts, including heart-draining lymphoid nodes, with a phenotype of promoting infarct repair, indicating a unique characteristic. The heart Tregs were accumulated mainly because of recruitment from the circulating Treg pool, whereas local proliferation also contributed to their expansion. Moreover, a remarkable case of repeatedly detected T-cell receptor of heart Tregs, more than that of spleen Tregs, suggests a model of clonal expansion. Besides, Helios high Nrp-1 high phenotype proved the mainly thymic origin of heart Tregs, with a small contribution of phenotypic conversion of conventional CD4 + T cells, proved by the analysis of T-cell receptor repertoires and conventional CD4 + T cells adoptive transfer experiments. The interleukin-33/suppression of tumorigenicity 2 axis was essential for sustaining heart Treg populations. Last, we demonstrated that Sparc, which was highly expressed by heart Tregs, acted as a critical factor to protect the heart against MI by increasing collagen content and boosting maturation in the infarct zone. Conclusions: We identified and characterized a phenotypically and functionally unique population of heart Tregs that may lay the foundation to harness Tregs for cardioprotection in MI and other cardiac diseases.

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Netrin-1 reduces lung ischemia-reperfusion injury by increasing the proportion of regulatory T cells

Journal of International Medical Research ◽

10.1177/0300060520926415 ◽

2020 ◽

Vol 48 (6) ◽

pp. 030006052092641

Author(s):

Zhili Chen ◽

Yuxi Chen ◽

Jue Zhou ◽

Yong Li ◽

Changyao Gong ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

Regulatory T Cells ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Axonal Guidance ◽

Terminal Deoxynucleotidyl Transferase ◽

Treg Depletion

Objective Inflammation is the primary mechanism of lung ischemia-reperfusion injury (LIRI) and neurologic factors can regulate inflammatory immune responses. Netrin-1 is an axonal guidance molecule, but whether Netrin-1 plays a role in LIRI remains unclear. Methods A mouse model of LIRI was established. Immunohistochemistry was used to detect expression of Netrin-1 and to enumerate macrophages and T cells in lung tissue. The proportion of regulatory T cells (Tregs) was assessed by flow cytometry. Levels of apoptosis were assessed by terminal deoxynucleotidyl transferase dUTP nick end staining. Results Numbers of macrophages and T cells in the lung tissues of mice with LIRI were elevated, while expression of netrin-1 was significantly decreased. Flow cytometry showed that the proportion of Tregs in mice with LIRI was significantly decreased. The proportion of Tregs among lymphocytes was positively correlated with netrin-1 expression. In vitro experiments showed that netrin-1 promoted an increase in Treg proportion through the A2b receptor. Animal experiments showed that netrin-1 could inhibit apoptosis and reduce T cell and macrophage infiltration by increasing the proportion of Tregs, ultimately reducing LIRI. Treg depletion using an anti-CD25 monoclonal antibody blocked the effects of netrin-1. Conclusion Netrin-1 reduced LIRI by increasing the proportion of Tregs.

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