Role of Metabolism in the Immunobiology of Regulatory T Cells

Galgani, Mario; Rosa, Veronica De; Cava, Antonio La; Matarese, Giuseppe

doi:10.4049/jimmunol.1600242

Cited by 99 publications

(88 citation statements)

References 123 publications

(171 reference statements)

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“…This concept has been fueled by several experimental studies demonstrating that modulation of immune metabolism can shape immune responses and thus ameliorate autoimmunity in different animal models (17,(50)(51)(52). One intriguing example is the illustration of differential metabolic demands of effector versus regulatory T cell subsets (52)(53)(54). In this line, we could demonstrate that Th1 cells display a larger capacity for OXPHOS as well as glycolysis compared to Th17 cells, which might render them more susceptible towards DHODH-mediated effects (Fig.…”

Section: Comparison Of Metabolic Profiles Of Activated High-affinity mentioning

confidence: 99%

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects

et al. 2019

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Interference with immune cell proliferation represents a successful treatment strategy in T cell–mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (MS). One prominent example is pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which mediates de novo pyrimidine synthesis in actively proliferating T and B lymphocytes. Within the TERIDYNAMIC clinical study, we observed that the DHODH inhibitor teriflunomide caused selective changes in T cell subset composition and T cell receptor repertoire diversity in patients with relapsing-remitting MS (RRMS). In a preclinical antigen-specific setup, DHODH inhibition preferentially suppressed the proliferation of high-affinity T cells. Mechanistically, DHODH inhibition interferes with oxidative phosphorylation (OXPHOS) and aerobic glycolysis in activated T cells via functional inhibition of complex III of the respiratory chain. The affinity-dependent effects of DHODH inhibition were closely linked to differences in T cell metabolism. High-affinity T cells preferentially use OXPHOS during early activation, which explains their increased susceptibility toward DHODH inhibition. In a mouse model of MS, DHODH inhibitory treatment resulted in preferential inhibition of high-affinity autoreactive T cell clones. Compared to T cells from healthy controls, T cells from patients with RRMS exhibited increased OXPHOS and glycolysis, which were reduced with teriflunomide treatment. Together, these data point to a mechanism of action where DHODH inhibition corrects metabolic disturbances in T cells, which primarily affects profoundly metabolically active high-affinity T cell clones. Hence, DHODH inhibition may promote recovery of an altered T cell receptor repertoire in autoimmunity.

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Section: Comparison Of Metabolic Profiles Of Activated High-affinity mentioning

confidence: 99%

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects

et al. 2019

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“…Recent observations suggest that Teff cells and Tregs require completely distinct metabolic pathways for their proliferation and activity. 54 T effector cells are highly glycogenic and have high Glut-1 levels on their surface. 55 In mice and humans, the high glycolytic rate is due to hyper-activation of the mTOR signaling pathway and is operative during nutrient-deprived conditions.…”

Section: Factors Influencing Treg Level Activity and Intra-tumoral mentioning

confidence: 99%

<p>T-Regulatory Cells In Tumor Progression And Therapy</p>

Verma

Mathur

Farooque

et al. 2019

CMAR

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Regulatory T cells (Tregs) are important members of the immune system regulating the host responses to infection and neoplasms. Tregs prevent autoimmune disorders by protecting the host-cells from an immune response, related to the peripheral tolerance. However, tumor cells use Tregs as a shield to protect themselves against anti-tumor immune response. Thus, Tregs are a hurdle in achieving the complete potential of anti-cancer therapies including immunotherapy. This has prompted the development of novel adjuvant therapies that obviate their negative effects thereby enhancing the therapeutic efficacy. Our earlier studies have shown the efficacy of the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG) by reducing the induced Tregs pool and enhance immune stimulation as well as local tumor control. These findings have suggested its potential for enhancing the efficacy of immunotherapy, besides radiotherapy and chemotherapy. This review provides a brief account of the current status of Tregs as a component of the immune-biology of tumors and various preclinical and clinical strategies pursued to obviate the limitations imposed by them in achieving therapeutic efficacy.

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“…Comparing intratumoral Tregs and cytotoxic CD4 + T cells; in addition to increased anti-inflammatory gene program, the Tregs displayed an enrichment in metabolic pathway genes set associated with glycolysis, glycogen metabolism and TCA cycle to fuel oxidative phosphorylation ( Fig. S3E) required for Treg suppressive function (42).…”

Section: In-depth Characterization Of Cd4 T Cells In Ccrcc Tumors Revmentioning

confidence: 99%

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

Vishwakarma

Borcherding

Chimenti

et al. 2019

Preprint

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One Sentence Summary: Single-cell RNA-sequencing reveals unique lymphoid and myeloid gene programs with putative functions in clear cell renal cancer patients Abstract: The immune cells within the tumor microenvironment are considered key determinants of response to cancer immunotherapy. Immune checkpoint blockade (ICB) has transformed the treatment of clear cell renal cell carcinoma (ccRCC), although the role of specific immune cell states remains unclear. To characterize the tumor microenvironment (TME) of ccRCC, we applied single-cell RNA sequencing (scRNA-seq) along with paired T cell receptor sequencing to map the transcriptomic heterogeneity of 24,904 individual CD45 + lymphoid and myeloid cells in matched tumor and blood from patients with ccRCC. We identified multiple distinct immune cell phenotypes for B and T (CD4 and CD8) lymphocytes, natural kill (NK) cells, and myeloid cells. Evaluation of T cell receptor (TCR) sequences revealed limited shared clonotypes between patients, whereas tumor-infiltrating T cell clonotypes were frequently found in peripheral blood, albeit in lower abundance. We further show that the circulating CD4 + T cell clonality is far less diverse than peripheral CD8 + . Evaluation of myeloid subsets revealed unique gene programs defining monocytes, dendritic cells and tumor-associated macrophages. In summary, here we have leveraged scRNA-seq to refine our understanding of the relative abundance, diversity and complexity of the immune landscape of ccRCC. This report represents the first characterization of ccRCC immune landscape using scRNA-seq. With further characterization and functional validation, these findings may identify novel sub-populations of immune cells amenable to therapeutic intervention. [Main Text:]

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Role of Metabolism in the Immunobiology of Regulatory T Cells

Cited by 99 publications

References 123 publications

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects

<p>T-Regulatory Cells In Tumor Progression And Therapy</p>

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

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