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Inhibition of myeloid-derived suppressor cell arginase-1 production enhances T-cell-based immunotherapy against
Ya-Nan Li1,2, Zhong-Wei Wang2, Fan Li2
1Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Abstract:
Cryptococcosis is a potentially lethal disease that is primarily caused by the fungus Cryptococcus neoformans, treatment options for cryptococcosis are limited. Here, we show glucuronoxylomannan, the major polysaccharide component of C. neoformans, induces the recruitment of neutrophilic myeloid-derived suppressor cells in mice and patients with cryptococcosis. Depletion of neutrophilic myeloid-derived suppressor cells enhances host defense against C. neoformans infection. We identify C-type lectin receptor-2d recognizes glucuronoxylomannan to potentiate the immunosuppressive activity of neutrophilic myeloid-derived suppressor cells by initiating p38-mediated production of the enzyme arginase-1, which inhibits T-cell mediated antifungal responses. Notably, pharmacological inhibition of arginase-1 expression by a specific inhibitor of p38, SB202190, or an orally available receptor tyrosine kinase inhibitor, vandetanib, significantly enhances T-cell mediated antifungal responses against cryptococcosis. These data reveal a crucial suppressive role of neutrophilic myeloid-derived suppressor cells during cryptococcosis and highlight a promising immunotherapeutic application by inhibiting arginase-1 production to combat infectious diseases.
Insights
Glucuronoxylomannan from Cryptococcus neoformans recruits immunosuppressive cells. Inhibiting arginase-1 in these cells boosts antifungal immunity, offering a new therapeutic strategy for cryptococcosis.
Area of Science:
- Immunology
- Mycology
- Infectious Diseases
Background:
- Cryptococcosis, caused by Cryptococcus neoformans, is a life-threatening fungal infection with limited treatment options.
- Glucuronoxylomannan (GXM) is the primary polysaccharide component of C. neoformans, playing a key role in fungal pathogenesis.
Purpose of the Study:
- To investigate the role of GXM in modulating the host immune response during cryptococcosis.
- To identify the mechanisms by which GXM influences immune cells and to explore potential therapeutic targets.
Main Methods:
- Studies were conducted in mouse models of cryptococcosis and in patients with the disease.
- Flow cytometry and depletion strategies were used to analyze neutrophilic myeloid-derived suppressor cells (nMDSCs).
- Molecular techniques identified the interaction between GXM, C-type lectin receptor-2d, and p38-mediated arginase-1 production.
Main Results:
- GXM induces the recruitment of nMDSCs in both mice and patients with cryptococcosis.
- Depletion of nMDSCs significantly improves host defense against C. neoformans infection.
- C-type lectin receptor-2d recognizes GXM, leading to p38-mediated arginase-1 production, which suppresses T-cell antifungal responses.
Conclusions:
- nMDSCs play a critical immunosuppressive role in cryptococcosis by producing arginase-1.
- Pharmacological inhibition of arginase-1, via p38 inhibitors (e.g., SB202190) or receptor tyrosine kinase inhibitors (e.g., vandetanib), enhances T-cell mediated antifungal responses.
- Targeting arginase-1 represents a promising immunotherapeutic strategy for cryptococcosis and other infectious diseases.
