T-cell-mediated immunodeficiency caused by anti-interferon-γ autoantibodies promotes the pathogenesis of Talaromycosis marneffei
- 1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
- 2Guangzhou National Laboratory, Bio-Island, Guangzhou, China
- 3Guangdong Laboratory Animals Monitoring Institute and Guangdong Provincial Key Laboratory of Laboratory Animals, Guangzhou, China
Abstract
Anti-interferon-γ autoantibody (AIGA)-associated adult-onset immunodeficiency is an important underlying condition in patients with severe talaromycosis caused by Talaromyces marneffei, but the mechanisms underlying impaired antifungal immunity remain incompletely understood. This study aimed to define the contributions of CD4⁺ T cells, CD8⁺ T cells, and IFN-γ-dependent immune signaling to host defense against T. marneffei. We used an intranasal BALB/c mouse infection model with antibody-mediated CD4⁺ T-cell depletion, CD8⁺ T-cell depletion, or IFN-γ neutralization, together with immunological assays using sera from AIGA-positive patients and healthy controls. In mice, T. marneffei infection induced stronger and more sustained T-cell activation in the lungs than in the spleen, with pulmonary CD4⁺ T-cell activation representing the predominant response and CD8⁺ T cells showing distinct temporal kinetics. Depletion of CD4⁺ or CD8⁺ T cells, or blockade of IFN-γ, impaired body-weight recovery and reduced survival, aggravated pulmonary and splenic injury, and delayed fungal clearance. In clinical immunological assays involving 28 AIGA-positive patients and 30 healthy controls, depletion of IgG from AIGA-positive sera restored IFN-γ⁺TNF-α⁺ CD4⁺ and CD8⁺ T-cell responses toward healthy-control levels, suggesting that patient IgG suppresses T-cell cytokine responses. AIGA-positive sera contained IgG that bound IFN-γ and attenuated IFN-γ-induced STAT1 phosphorylation and HLA-DR upregulation in THP-1 cells, supporting functional neutralization of IFN-γ signaling and impaired antigen-presenting cell activation. Together, these findings indicate that AIGA-associated talaromycosis involves impaired IFN-γ-dependent coordination of innate effector functions and T-cell responses. Clinically, they support consideration of AIGA-associated adult-onset immunodeficiency in HIV-negative patients with severe or disseminated talaromycosis, particularly in endemic regions, and provide a rationale for future studies aimed at restoring IFN-γ bioactivity. Author summary: Talaromycosis is a potentially life-threatening invasive fungal disease caused by Talaromyces marneffei, a thermally dimorphic fungus that is endemic in parts of Southeast Asia and southern China. Severe or disseminated talaromycosis can occur in HIV-negative patients with anti-interferon-γ autoantibody (AIGA)-associated adult-onset immunodeficiency, a condition that disrupts an important pathway of antifungal immunity. However, why these patients develop severe disease remains incompletely understood. Using a mouse model of T. marneffei infection, we found that both CD4⁺ and CD8⁺ T cells were activated during infection. CD4+ T cells represented the predominant responding population, whereas pulmonary CD8⁺ T-cell responses developed earlier. Blocking IFN-γ or depleting CD4⁺ or CD8⁺ T cells resulted in greater weight loss, lower survival, more severe disease, and delayed fungal clearance.. To investigate the relevance of these findings to human disease, we analyzed blood samples from AIGA-positive patients. Removing IgG from patient sera increased IFN-γ⁺TNF-α⁺ CD4⁺ and CD8⁺ T-cell responses. Patient-derived IgG also attenuated IFN-γ-induced STAT1 phosphorylation and HLA-DR expression in THP-1 cells, indicating impaired IFN-γ-dependent signaling and antigen-presentation-related responses. Our findings suggest that AIGA-associated IgG weakens several immune defenses needed to control T. marneffei. Recognizing this condition in HIV-negative patients with severe talaromycosis may help explain poor fungal clearance and guide future studies of treatments that restore IFN-γ activity.
Related
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BibTeX
@article{yang2026tcellmediated,
title = {{T-cell-mediated immunodeficiency caused by anti-interferon-γ autoantibodies promotes the pathogenesis of Talaromycosis marneffei}},
author = {Jinglu Yang and Zhengtu Li and Xiao-Yun Yang and Shao-Qiang Li and Feng Cong and Chun Lu and Haoru Wang and Xidong Wang and Yuanxiang Li and Zhong-Fang Wang and Feng Ye},
journal = {PLOS Neglected Tropical Diseases},
year = {2026},
month = nov,
doi = {10.1371/journal.pntd.0014793},
url = {https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014793},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - T-cell-mediated immunodeficiency caused by anti-interferon-γ autoantibodies promotes the pathogenesis of Talaromycosis marneffei
AU - Jinglu Yang
AU - Zhengtu Li
AU - Xiao-Yun Yang
AU - Shao-Qiang Li
AU - Feng Cong
AU - Chun Lu
AU - Haoru Wang
AU - Xidong Wang
AU - Yuanxiang Li
AU - Zhong-Fang Wang
AU - Feng Ye
PY - 2026
DA - 2026/11/03
JO - PLOS Neglected Tropical Diseases
DO - 10.1371/journal.pntd.0014793
UR - https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014793
AB - Anti-interferon-γ autoantibody (AIGA)-associated adult-onset immunodeficiency is an important underlying condition in patients with severe talaromycosis caused by Talaromyces marneffei, but the mechanisms underlying impaired antifungal immunity remain incompletely understood. This study aimed to define the contributions of CD4⁺ T cells, CD8⁺ T cells, and IFN-γ-dependent immune signaling to host defense against T. marneffei. We used an intranasal BALB/c mouse infection model with antibody-mediated CD4⁺ T-cell depletion, CD8⁺ T-cell depletion, or IFN-γ neutralization, together with immunological assays using sera from AIGA-positive patients and healthy controls. In mice, T. marneffei infection induced stronger and more sustained T-cell activation in the lungs than in the spleen, with pulmonary CD4⁺ T-cell activation representing the predominant response and CD8⁺ T cells showing distinct temporal kinetics. Depletion of CD4⁺ or CD8⁺ T cells, or blockade of IFN-γ, impaired body-weight recovery and reduced survival, aggravated pulmonary and splenic injury, and delayed fungal clearance. In clinical immunological assays involving 28 AIGA-positive patients and 30 healthy controls, depletion of IgG from AIGA-positive sera restored IFN-γ⁺TNF-α⁺ CD4⁺ and CD8⁺ T-cell responses toward healthy-control levels, suggesting that patient IgG suppresses T-cell cytokine responses. AIGA-positive sera contained IgG that bound IFN-γ and attenuated IFN-γ-induced STAT1 phosphorylation and HLA-DR upregulation in THP-1 cells, supporting functional neutralization of IFN-γ signaling and impaired antigen-presenting cell activation. Together, these findings indicate that AIGA-associated talaromycosis involves impaired IFN-γ-dependent coordination of innate effector functions and T-cell responses. Clinically, they support consideration of AIGA-associated adult-onset immunodeficiency in HIV-negative patients with severe or disseminated talaromycosis, particularly in endemic regions, and provide a rationale for future studies aimed at restoring IFN-γ bioactivity. Author summary: Talaromycosis is a potentially life-threatening invasive fungal disease caused by Talaromyces marneffei, a thermally dimorphic fungus that is endemic in parts of Southeast Asia and southern China. Severe or disseminated talaromycosis can occur in HIV-negative patients with anti-interferon-γ autoantibody (AIGA)-associated adult-onset immunodeficiency, a condition that disrupts an important pathway of antifungal immunity. However, why these patients develop severe disease remains incompletely understood. Using a mouse model of T. marneffei infection, we found that both CD4⁺ and CD8⁺ T cells were activated during infection. CD4+ T cells represented the predominant responding population, whereas pulmonary CD8⁺ T-cell responses developed earlier. Blocking IFN-γ or depleting CD4⁺ or CD8⁺ T cells resulted in greater weight loss, lower survival, more severe disease, and delayed fungal clearance.. To investigate the relevance of these findings to human disease, we analyzed blood samples from AIGA-positive patients. Removing IgG from patient sera increased IFN-γ⁺TNF-α⁺ CD4⁺ and CD8⁺ T-cell responses. Patient-derived IgG also attenuated IFN-γ-induced STAT1 phosphorylation and HLA-DR expression in THP-1 cells, indicating impaired IFN-γ-dependent signaling and antigen-presentation-related responses. Our findings suggest that AIGA-associated IgG weakens several immune defenses needed to control T. marneffei. Recognizing this condition in HIV-negative patients with severe talaromycosis may help explain poor fungal clearance and guide future studies of treatments that restore IFN-γ activity.
SN - 1935-2735
ER -