Human Endothelial Cells Modulate CD4+ T Cell Populations and Enhance Regulatory T Cell Suppressive Capacity

Lim, Wen Chean; Olding, Michael; Healy, Eugene; Millar, Timothy M.

doi:10.3389/fimmu.2018.00565

Cited by 42 publications

(43 citation statements)

References 57 publications

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“…Prominent roles of CD4 + T cells in chronic diseases have been reported in previous studies ( 52 , 53 ). Our colleagues showed that massive CD4 + T lymphocyte infiltration was observed in the fibrotic kidneys of patients and UUO mice ( 54 ).…”

Section: Discussionsupporting

confidence: 64%

Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion

et al. 2018

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Complement synthesis in cells of origin is strongly linked to the pathogenesis and progression of renal disease. Multiple studies have examined local C3 synthesis in renal disease and elucidated the contribution of local cellular sources, but the contribution of infiltrating inflammatory cells remains unclear. We investigate the relationships among C3, macrophages and Th17 cells, which are involved in interstitial fibrosis. Here, we report that increased local C3 expression, mainly by monocyte/macrophages, was detected in renal biopsy specimens and was correlated with the severity of renal fibrosis (RF) and indexes of renal function. In mouse models of UUO (unilateral ureteral obstruction), we found that local C3 was constitutively expressed throughout the kidney in the interstitium, from which it was released by F4/80+macrophages. After the depletion of macrophages using clodronate, mice lacking macrophages exhibited reductions in C3 expression and renal tubulointerstitial fibrosis. Blocking C3 expression with a C3 and C3aR inhibitor provided similar protection against renal tubulointerstitial fibrosis. These protective effects were associated with reduced pro-inflammatory cytokines, renal recruitment of inflammatory cells, and the Th17 response. in vitro, recombinant C3a significantly enhanced T cell proliferation and IL-17A expression, which was mediated through phosphorylation of ERK, STAT3, and STAT5 and activation of NF-kB in T cells. More importantly, blockade of C3a by a C3aR inhibitor drastically suppressed IL-17A expression in C3a-stimulated T cells. We propose that local C3 secretion by macrophages leads to IL-17A-mediated inflammatory cell infiltration into the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the C3a/C3aR pathway is a novel therapeutic approach for obstructive nephropathy.

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Section: Discussionsupporting

confidence: 64%

Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion

et al. 2018

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“…The immunosuppressive function of Treg is modulated by plenty of mechanisms, including direct engagement with cells through costimulatory signals via OX40, PD-1 and their ligands and indirectly by cytokine through TGF-β and IL-10 34. Endothelial cells (ECs) exert important effect on immunocyte recruitment and activation.…”

Section: The Role Of Pd-1/pd-l1 Axis In Treg Development and Functionmentioning

confidence: 99%

<p>The Role Of PD-1/PD-L1 Axis In Treg Development And Function: Implications For Cancer Immunotherapy</p>

Cai

Wang

Zhang

et al. 2019

OTT

166

118

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During the past decade, immunotherapy targeting immune checkpoints has become an important component of the treatment paradigm for numerous malignancies, especially PD-1/ PD-L1 blockade which was demonstrated to rejuvenate disabled T cells in cancer patients to achieve long-term remissions. However, the clinical outcome of PD-1/PD-L1 targeted monotherapy against solid malignancies is not satisfactory which may be related with the intricate tumor microenvironment. As a vital suppressive immunocyte in tumor microenvironment, Tregs are characterized by PD-1 and PD-L1 and demonstrated to contribute to the tumor progression. The latest studies have suggested that Tregs might be involved in the treatment of PD-1/PD-L1 blockade and PD-1/PD-L1 axis could influence Treg differentiation and function. However, the complicated relationship between PD-1/PD-L1 pathway and Tregs has not been fully clarified. Here, we explored the role of PD-1/PD-L1 axis in Treg development and function, as well as the potential mechanisms of PD-1/PD-L1 blockade resistance related with Tregs. Meanwhile, we discussed the combination therapy aimed at targeting PD-1/PD-L1 axis and Tregs, hoping to provide novel insights for the future cancer treatment.

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“…Thus, we speculate that the interaction between Tregs and macrophages may be involved in tissue repair and pulmonary fibrosis induced by radiation, which warrants further investigation. Additionally, the interaction between Tregs and endothelial cells (ECs) has attracted special attention due to its potential involvement in the regulation of inflammation (91)(92)(93). Human umbilical vein endothelial cells co-cultured with Tregs show a diminished capacity to respond to lipopolysaccharide in terms of adhesion molecule expression and pro-inflammatory cytokine production (e.g., monocyte chemoattractant protein-1 and IL-6), suggesting a protective role of Tregs during inflammation (93).…”

Section: Therapeutic Implications and Future Directionsmentioning

confidence: 99%

Regulatory T Cells: An Emerging Player in Radiation-Induced Lung Injury

Guo

Zou

et al. 2020

Front. Immunol.

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Regulatory T cells (Tregs), which have long been recognized as essential regulators of both inflammation and autoimmunity, also impede effective antitumor immune response due to their immunosuppressive properties. Combined radiotherapy and immunotherapeutic interventions focusing on the removal of Tregs have recently garnered interest as a promising strategy to reverse immunosuppression. Meanwhile, Tregs are emerging as a key player in the pathogenesis of radiation-induced lung injury (RILI), a frequent and potentially life-threatening complication of thoracic radiotherapy. Recognition of the critical role of Tregs in RILI raises the important question of whether radiotherapy combined with Treg-targeting immunotherapy offers any beneficial effects in the protection of normal lung tissue. This present review focuses on the contributions of Tregs to RILI, with particular emphasis on the suspected differential role of Tregs in the pneumonitic phase and fibrotic phase of RILI. We also introduce recent progress on the potential mechanisms by which Tregs modulate RILI and the crosstalk among Tregs, other infiltrating T cells, fibrocytes, and resident epithelial cells driving disease pathogenesis. Finally, we discuss whether Tregs also hold promise as a potential target for immunotherapeutic interventions for RILI.

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Human Endothelial Cells Modulate CD4+ T Cell Populations and Enhance Regulatory T Cell Suppressive Capacity

Cited by 42 publications

References 57 publications

Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion

Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion

<p>The Role Of PD-1/PD-L1 Axis In Treg Development And Function: Implications For Cancer Immunotherapy</p>

Regulatory T Cells: An Emerging Player in Radiation-Induced Lung Injury

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