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Updated: Jun 28, 2025
Generation of Induced Regulatory T Cells from Primary Human Naïve and Memory T Cells
Published on: April 16, 2012
Cenicriviroc, a CCR2/CCR5 antagonist, promotes the generation of type 1 regulatory T cells
Upasna Madan1, Bhawna Verma1, Amit Awasthi1,2
1Centre for Immuno-biology and Immunotherapy, NCR-Biotech Science Cluster, Translational Health Science and Technology Institute, Faridabad, Haryana, India.
Abstract:
Cenicriviroc, a dual CCR2/CCR5 antagonist, initially developed as an anti-HIV drug, has shown promising results in nonalcoholic steatohepatitis phase 2 clinical trials. It inhibits the infiltration and activation of CCR2+/CCR5+ monocytes and macrophages to the site of liver injury, preventing liver fibrosis. However, the role of Cenicriviroc in the modulation of helper T cell differentiation and functions remains to be explored. In inflamed colons of Crohn's disease patients, CCR2+ and CCR5+ CD4+ T cells are enriched. Considering the role of CCR2+ and CCR5+ T cells in IBD pathogenesis, we investigated the potential role of Cenicriviroc in colitis. Our in vitro studies revealed that Cenicriviroc inhibits Th1-, Th2-, and Th17-cell differentiation while promoting the generation of type 1 regulatory T cells (Tr1), known for preventing inflammation through induction of IL-10. This study is the first to report that Cenicriviroc promotes Tr1 cell generation by up-regulating the signature of Tr1 cell transcription factors such as c-Maf, Prdm1, Irf-1, Batf, and EGR-2. Cenicriviroc displayed a protective effect in experimental colitis models by preventing body weight loss and intestinal inflammation and preserving epithelial barrier integrity. We show that Cenicriviroc induced IL-10 and inhibited the generation of pro-inflammatory cytokines IFN-γ, IL-17, IL-6, and IL-1β during colitis. Based on our data, we propose Cenicriviroc as a potential therapeutic in controlling tissue inflammation by inhibiting the generation and functions of effector T cells and promoting the induction of anti-inflammatory Tr1 cells.
Insights
Cenicriviroc, an anti-HIV drug, shows potential for treating inflammatory bowel disease. It inhibits inflammatory T cells while promoting regulatory T cells, reducing gut inflammation and protecting the intestinal barrier.
Area of Science:
- Immunology
- Gastroenterology
- Pharmacology
Background:
- Cenicriviroc (CVC) is a dual CCR2/CCR5 antagonist initially developed for HIV treatment.
- CVC has shown efficacy in nonalcoholic steatohepatitis (NASH) by inhibiting monocyte/macrophage infiltration and liver fibrosis.
- CCR2+ and CCR5+ CD4+ T cells are implicated in Inflammatory Bowel Disease (IBD) pathogenesis.
Purpose of the Study:
- To investigate the role of Cenicriviroc in modulating helper T cell differentiation and function in the context of colitis.
- To explore Cenicriviroc's potential therapeutic effects in experimental colitis models.
Main Methods:
- In vitro studies assessing T cell differentiation (Th1, Th2, Th17, Tr1) in the presence of Cenicriviroc.
- Analysis of key transcription factors for Tr1 cell generation (c-Maf, Prdm1, Irf-1, Batf, EGR-2).
- In vivo assessment of Cenicriviroc's efficacy in experimental colitis models, evaluating body weight, intestinal inflammation, and epithelial barrier integrity.
Main Results:
- Cenicriviroc inhibited Th1, Th2, and Th17 cell differentiation in vitro.
- Cenicriviroc promoted the generation of type 1 regulatory T cells (Tr1) by upregulating specific transcription factors.
- Cenicriviroc demonstrated protective effects in experimental colitis, reducing inflammation, preserving barrier integrity, and inducing IL-10 while inhibiting pro-inflammatory cytokines (IFN-γ, IL-17, IL-6, IL-1β).
Conclusions:
- Cenicriviroc modulates helper T cell differentiation, favoring the induction of anti-inflammatory Tr1 cells.
- Cenicriviroc exhibits therapeutic potential for colitis by inhibiting effector T cell functions and promoting regulatory T cell induction.
- Cenicriviroc represents a promising therapeutic candidate for controlling tissue inflammation in IBD.
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