Anti-Interferon-γ Autoantibodies Impair T-Lymphocyte Responses in Patients with Talaromyces marneffei Infections

Abstract

Zhao-Ming Chen,1,* Xiao-Yun Yang,1,2,* Zheng-Tu Li,1,* Wei-Jie Guan,1,3 Ye Qiu,4 Shao-Qiang Li,1 Yang-Qing Zhan,1 Zi-Ying Lei,5 Jing Liu,4 Jian-Quan Zhang,6 Zhong-Fang Wang,1,2 Feng Ye1 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, Guangdong, People’s Republic of China; 2Guangzhou Laboratory, Bio-Island, Guangzhou, Guangdong, People’s Republic of China; 3Department of Thoracic Surgery, Guangzhou Institute for Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 4Department of Comprehensive Internal Medicine, the Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 5Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China; 6Department of Infectious Diseases, the Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Feng Ye, 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, Guangdong, 510120, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected]: Although anti-IFN-γ autoantibodies predispose patients to Talaromyces marneffei infection, whether this is mediated by T cell attenuation remains elusive.Methods: Total peripheral blood mononuclear cells (PBMCs) from healthy donors or patients with T. marneffei infection were stimulated with M158− 66, and immunodominant influenza H1N1 peptide, or heat-inactivated T. marneffei in the presence of serum from anti-IFN-γ autoantibody-positive patients or healthy controls. The percentages of IFN-γ+TNF+CD8+ T cells and IFN-γ+CD4+ T cells were determined by flow cytometry and cytokines released in the supernatant were detected by Cytometric Bead Array. Furthermore, PBMCs from patients with T. marneffei infection and healthy individuals were stimulated with IFN-γ and anti-CD3/CD28 beads, and the levels of STAT1 and STAT3 phosphorylation were detected by Western blot.Results: The M1-reactive CD8+ T cells that expressed IFN-γ+ TNF-α+ of healthy controls were clearly reduced in serum with high-titer anti-IFN-γ autoantibodies. In addition, the CD4+ T cell response, designated by the expression of IFN-γ, against T. marneffei in PBMCs of patients were significantly decreased when cultured in high-titer anti-IFN-γ autoantibody serum culture, compared to the healthy compartments. Moreover, the release of the cytokines IFN-γ, TNF-α and IL-2 was significantly decreased, while IL-10 was significantly increased. There was no significant difference in the phosphorylation levels of STAT1 and STAT3 protein between patients and healthy controls after IFN-γ or anti-CD3/CD28 beads stimulation.Conclusion: Anti-IFN-γ autoantibodies presence in the serum inhibited CD4+ Th1 and CD8+ T cell immune responses. There was no congenital dysfunction of STAT1 and STAT3 in anti-IFN-γ autoantibody-positive patients with T. marneffei infection. These results suggest that the production of anti-IFN-γ autoAbs impair T-lymphocyte responses.Keywords: anti-interferon-γ autoantibody, T lymphocyte, Talaromyces marneffei, signal transducer and activator of transcription 1, signal transducer and activator of transcription 3

Keywords

• anti-interferon-γ autoantibody
• t lymphocyte
• talaromyces marneffei
• signal transducer and activator of transcription 1
• signal transducer and activator of transcription 3