TREM2+ macrophages recognize candidalysin to launch early antifungal immunity

A research team led by Professor Yunsheng Liang at the Second Xiangya Hospital of Central South University, Professor Yingping Xu at the Dermatology Hospital of Southern Medical University, and Associate Professor Xiaowen Wang at Peking University First Hospital has uncovered a previously unknown mechanism by which the innate immune system detects Candida albicans infection. Published in Volume 2, article number 25 of the journal Immunity & Inflammation on May 18, 2026, the study demonstrates that a subset of macrophages expressing the receptor TREM2 (triggering receptor expressed on myeloid cells-2) directly recognizes candidalysin—a toxin secreted by the fungus—to initiate a rapid and protective immune response.

Oropharyngeal candidiasis (OPC) is one of the most common mucosal fungal infections in immunocompromised patients, leading to reduced quality of life, malnutrition, and increased risk of systemic infection. Macrophages serve as key effector cells against OPC, yet the molecular mechanisms by which they detect and respond to Candida have been incompletely understood. TREM2 is known to be a sensor of tissue damage and a regulator of immune responses in various diseases, but its role in fungal infection was almost entirely unknown.

Using single-cell transcriptomic sequencing—the first such study in the oral mucosa of a mouse OPC model—the team mapped the immune landscape of the tongue following Candida infection. The results revealed a marked infiltration of monocyte-derived TREM2⁺ macrophages into the infected lingual epithelium. Using multiple genetic models, including global TREM2 knockout, myeloid-specific TREM2 deletion, and TREM2-DTR cell depletion, the researchers demonstrated that loss of this cell population significantly increased susceptibility to OPC, establishing TREM2⁺ macrophages as essential for antifungal immunity.

A long-standing question in the field has been how candidalysin—a secreted peptide toxin critical for Candida virulence—is detected by the host immune system. The study provides the first evidence that TREM2 directly binds candidalysin. Surface plasmon resonance (SPR) and microscale thermophoresis (MST) confirmed the physical interaction. Furthermore, using AlphaFold molecular docking and site-directed mutagenesis, the team identified key binding residues on TREM2 (D131, R136, P169) and corresponding residues on candidalysin (G65, N73, N91-K92). This discovery reveals how the host exploits a pathogen toxin as an “alarm signal” to mount a defense.

Mechanistically, upon recognition of candidalysin, TREM2 primarily recruits the adaptor protein DAP12, leading to the activation of Syk kinase, subsequent phosphorylation of NF-κB p65 and MAPK p38, and ultimately secretion of TNF-α. TNF-α acts in an autocrine manner to enhance macrophage phagocytosis, killing, and reactive oxygen species production. In a paracrine manner, TNF-α promotes neutrophil extracellular trap (NET) formation and bactericidal function, while moderately modulating IL-17 signaling from TCRαβ⁺ cells. “These data establish the TREM2–candidalysin–TNF-α axis as a central regulatory pathway in early innate immunity against OPC,” the authors outlined.

This discovery provides a new dimension for understanding how the immune system distinguishes self from harmful pathogens and identifies a novel node connecting innate and adaptive antifungal immunity. “It also offers multiple translational opportunities,” the authors concluded: “First, TREM2 itself could serve as a drug target; TREM2 agonists or candidalysin mimetics might be developed to activate local innate defense. Second, for immunocompromised patients (e.g., after CAR-T therapy or chemotherapy), enhancing TREM2 signaling could be an immune-adjuvant strategy to prevent OPC. Third, the identified epitope on candidalysin recognized by TREM2 could be a candidate vaccine antigen, potentially inducing protective immune memory. Finally, TREM2 or candidalysin levels in oral mucosa might serve as biomarkers to assess OPC risk and prognosis.”

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Reference
DOI: 10.1007/s44466-026-00041-5  

About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.

Website: https://link.springer.com/journal/44466

About Professor Yunsheng Liang from Central South University, China
Professor Yunsheng Liang is the Director of the Department of Dermatology and Venereology at the Second Xiangya Hospital of Central South University and a principal investigator at the Hunan Key Laboratory of Medical Epigenomics. He has published over 40 research papers as a first or corresponding author in journals, including J Am Acad Dermatol, Allergy, J Allergy Clin Immunol, and APSB. His research focuses on epigenetic mechanisms and translational research in immune-mediated skin diseases.

About Professor Yingping Xu from Southern Medical University, China
Yingping Xu is a Professor at the Dermatology Hospital of Southern Medical University. She serves as a committee member of the Immunology Group of the Chinese Society of Dermatology and Venereology and a council member of the Guangdong Society for Human Genetic Resources Preservation and Application. Her research focuses on regulatory mechanisms of skin immunity and skin regeneration.

About Professor Xiaowen Wang from Peking University First Hospital, China
Xiaowen Wang is an Associate Professor in the Department of Dermatology and Venereology at Peking University First Hospital and the Deputy Director of the Peking University Research Center for Fungi and Fungal Diseases. She is the Vice Chair of the Mycology Group of the Chinese Society of Dermatology and Venereology. She has been recognized as a recipient of the National High-Level Young Talent Program and the Young Talent Lifting Project of the China Association for Science and Technology. Her research focuses on fungal infection immunity.

Funding information
This work was supported by the National Natural Science Foundation of China (grant numbers: 82404157 and 81972941) and the key project of the National Natural Science Foundation of China (grant number: 82030095).