{ "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.", "abstract_shown": true, "affiliations": [ "State 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", "Guangzhou National Laboratory, Bio-Island, Guangzhou, China", "Guangdong Laboratory Animals Monitoring Institute and Guangdong Provincial Key Laboratory of Laboratory Animals, Guangzhou, China" ], "article_type": "Research Article", "arxiv": null, "author_total": 11, "authors": [ { "affs": [ 0 ], "name": "Jinglu Yang" }, { "affs": [ 1 ], "name": "Zhengtu Li" }, { "affs": [ 2 ], "name": "Xiao-Yun Yang" }, { "name": "Shao-Qiang Li" }, { "name": "Feng Cong" }, { "name": "Chun Lu" }, { "name": "Haoru Wang" }, { "name": "Xidong Wang" }, { "name": "Yuanxiang Li" }, { "name": "Zhong-Fang Wang" }, { "name": "Feng Ye" } ], "bibtex": "https://research.draconitic.com/paper/1pw07a5g2ak9g.bib", "cited_by": 0, "doi": "10.1371/journal.pntd.0014793", "fulltext_url": "https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014793", "id": "1pw07a5g2ak9g", "issns": [ "1935-2735" ], "landing_url": "https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014793", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "plos", "/Biology and life sciences/Anatomy/Respiratory system/Lungs" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/T cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/T cells/Cytotoxic T cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/T helper cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/T cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/T cells/Cytotoxic T cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/T helper cells" ], [ "plos", "/Biology and life sciences/Developmental biology/Molecular development/Cytokines" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/T cells" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/T cells/Cytotoxic T cells" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/T helper cells" ], [ "plos", "/Biology and life sciences/Immunology/Immune system/Innate immune system/Cytokines" ], [ "plos", "/Biology and life sciences/Physiology/Immune physiology/Cytokines" ], [ "plos", "/Biology and life sciences/Physiology/Immune physiology/Spleen" ], [ "plos", "/Medicine and health sciences/Anatomy/Respiratory system/Lungs" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/T cells" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/T cells/Cytotoxic T cells" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/T helper cells" ], [ "plos", "/Medicine and health sciences/Immunology/Immune system/Innate immune system/Cytokines" ], [ "plos", "/Medicine and health sciences/Medical conditions/Infectious diseases/Fungal diseases" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Animal models/Mouse models" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Model organisms/Mouse models" ], [ "plos", "/Research and analysis methods/Model organisms/Mouse models" ] ], "openalex": null, "pdf_url": "https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0014793&type=printable", "pmcid": null, "pmid": null, "published": "2026-11-03", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/1pw07a5g2ak9g.ris", "sources": [ { "first_seen": "2026-11-04T12:20:43Z", "native_id": "10.1371/journal.pntd.0014793", "source": "plos", "url": "https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014793" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "medicine", "origin": "plos:anatomy", "subfield": "physiology" } ], "title": "T-cell-mediated immunodeficiency caused by anti-interferon-γ autoantibodies promotes the pathogenesis of Talaromycosis marneffei", "title_text": "T-cell-mediated immunodeficiency caused by anti-interferon-γ autoantibodies promotes the pathogenesis of Talaromycosis marneffei", "type": "peer-reviewed", "updated_at": "2026-11-05T12:20:11Z", "url": "https://research.draconitic.com/paper/1pw07a5g2ak9g", "venue": "PLOS Neglected Tropical Diseases", "versions": [] }