Role of Dynamic Actin Cytoskeleton Remodeling in Foxp3+ Regulatory T Cell Development and Function: Implications for Osteoclastogenesis

Dohnke, Sebastian; Moehser, Stephanie; Surnov, Alexey; Kurth, Thomas; Jessberger, Rolf; Kretschmer, Karsten; Garbe, Annette I.

doi:10.3389/fimmu.2022.836646

Cited by 2 publications

References 68 publications

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The pro-tumoral and anti-tumoral roles of EphA4 on T regulatory cells and tumor associated macrophages during HNSCC tumor progression

Corbo,

Nguyen,

Bhatia

et al. 2024

Preprint

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Head and Neck Squamous Cell Carcinoma (HNSCC) is a deadly cancer with poor response to targeted therapy, largely driven by an immunosuppressive tumor microenvironment (TME). Here we examine the immune-modulatory role of the receptor tyrosine kinase EphA4 in HNSCC progression. Within the TME, EphA4 is primarily expressed on regulatory T cells (Tregs) and macrophages. In contrast ephrinB2, an activating ligand of EphA4, is expressed in tumor blood vessels. Using genetically engineered mouse models, we show that EphA4 expressed in Tregs promotes tumor growth, whereas EphA4 expressed in monocytes inhibits tumor growth. In contrast, ephrinB2 knockout in blood vessels reduces both intratumoral Tregs and macrophages. A novel specific EphA4 inhibitor, APY-d3-PEG4, reverses the accelerated tumor growth we had previously reported with EphB4 cancer cell knockout. EphA4 knockout in macrophages not only enhanced their differentiation into M2 macrophage but also increased Treg suppressive activity. APY-d3-PEG4 reversed the accelerated growth seen in the EphA4 knockout of monocytes but conferred no additional benefit when EphA4 was knocked out on Tregs. Underscoring an EphA4-mediated interplay between Tregs and macrophages, we found that knockout of EphA4 in Tregs not only decreases their activation but also reduces tumor infiltration of pro-tumoral M2 macrophages. These data identify Tregs as a primary target of APY-d3-PEG4 and suggest a role for Tregs in regulating macrophage conversion. These data also support the possible anti-cancer therapeutic value of bispecific peptides or antibodies capable of promoting EphA4 blockade in Tregs but not macrophages.SignificanceEphA4 in regulatory T cells has a pro-tumoral effect while EphA4 in macrophages plays an anti-tumoral role underscoring the necessity of developing biologically rational therapeutics.

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The pro-tumoral and anti-tumoral roles of EphA4 on T regulatory cells and tumor associated macrophages during HNSCC tumor progression

Corbo,

Nguyen,

Bhatia

et al. 2024

Preprint

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Indoleamine 2,3-dioxygenase 1 signaling orchestrates immune tolerance in Echinococcus multilocularis-infected mice

Zhang

et al. 2022

Front. Immunol.

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The cestode Echinococcus multilocularis larva infection causes lethal zoonotic alveolar echinococcosis (AE), a disease posing a great threat to the public health worldwide. This persistent hepatic tumor-like disease in AE patients has been largely attributed to aberrant T cell responses, of which Th1 responses are impeded, whilst Th2 and regulatory T cell responses are elevated, creating an immune tolerogenic microenvironment in the liver. However, the immune tolerance mechanisms are not fully understood. Dendritic cells (DCs) are key cellular components in facilitating immune tolerance in chronic diseases, including AE. Here, we demonstrate that indoleamine 2,3-dioxygenase 1-deficient (IDO1-/-) mice display less severe AE as compared to wild-type (WT) mice during the infection. Mechanistically, IDO1 prevents optimal T cells responses by programming DCs into a tolerogenic state. Specifically, IDO1 prevents the maturation and migration potential of DCs, as shown by the significantly enhanced expression of the antigen-presenting molecule (MHC II), costimulatory molecules (CD80 and CD86), and chemokine receptors (CXCR4 and CCR7) in infected IDO1-/- mice as compared to infected wild-type mice. More importantly, the tolerogenic phenotype of DCs is partly reverted in IDO1-/- mice, as indicated by enhanced activation, proliferation, and differentiation of both CD4+ and CD8+ - T cells upon infection with Echinococcus multilocularis, in comparison with WT mice. Interestingly, in absence of IDO1, CD4+ T cells are prone to differentiate to effector memory cells (CD44+CD62L-); in contrast, CD8+ T cells are highly biased to the central memory phenotype (CD44+CD62L+). Overall, these data are the first to demonstrate the essential role of IDO1 signaling in inducing immunosuppression in mice infected with Echinococcus multilocularis.

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Role of Dynamic Actin Cytoskeleton Remodeling in Foxp3+ Regulatory T Cell Development and Function: Implications for Osteoclastogenesis

Cited by 2 publications

References 68 publications

The pro-tumoral and anti-tumoral roles of EphA4 on T regulatory cells and tumor associated macrophages during HNSCC tumor progression

The pro-tumoral and anti-tumoral roles of EphA4 on T regulatory cells and tumor associated macrophages during HNSCC tumor progression

Indoleamine 2,3-dioxygenase 1 signaling orchestrates immune tolerance in Echinococcus multilocularis-infected mice

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