Fas-Fas Ligand (CD95-CD95L) and Cytotoxic T Lymphocyte Antigen-4 Engagement Mediate T Cell Unresponsiveness in Patients with Paracoccidioidomycosis

• Published in: The Journal of infectious diseases 2003-05, Vol.187 (9), p.1496-1505
• Main Authors: Campanelli, Ana P, Martins, Gislâine A, Souto, Janeusa T, Pereira, Marcelo S. F, Livonesi, Márcia C, Martinez, Roberto, Silva, João S
• Format: Article
• Language: English
• Subjects: Abatacept; Adult; Antigens; Antigens, CD; Antigens, Differentiation - immunology; Antigens, Differentiation - metabolism; Apoptosis; B lymphocytes; Biological and medical sciences; Blastomycoses and paracoccidioidomycosis; Brazilian culture; Cell Division; Cell walls; Cells, Cultured; CTLA-4 Antigen; Cultured cells; Cytokines; Cytokines - metabolism; Fas Ligand Protein; fas Receptor - metabolism; Female; Fundamental and applied biological sciences. Psychology; Fungal antigens; Fungi; Gene Expression Regulation; Human mycoses; Humans; Immunoconjugates; Infectious diseases; Lymphocyte Activation; Male; Medical sciences; Membrane Glycoproteins - metabolism; Microbiology; Middle Aged; Mycology; Mycoses; Paracoccidioides; Paracoccidioidomycosis; Paracoccidioidomycosis - immunology; Paracoccidioidomycosis - metabolism; Pathogenicity, host-agent relations, miscellaneous strains, epidemiology; T lymphocytes; T-Lymphocytes, Cytotoxic - cytology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Tropical mycoses
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/374646

The mechanism that leads to the remarkable T cell unresponsiveness to antigens in paracoccidioidomycosis is unknown. We investigated the involvement of cytokines, of Fas-Fas ligand (Fas-FasL)-induced apoptosis, and of cytotoxic T lymphocyte antigen 4 (CTLA-4) engagement, in the mediation of this phenomenon. T cell unresponsiveness was not associated with imbalanced cytokine production or with absence of CD28 expression. Only patient T cells expressed higher levels of CTLA-4, Annexin V+, and FasL. The addition of anti-FasL decreased the levels of apoptosis, suggesting an activation-induced cell death triggered through the Fas-FasL pathway. Blockage of CTLA-4 and FasL resulted in increased production of interferon-γ. Moreover, concomitant inhibition of FasL and of CTLA-4, but not of transforming growth factor-β, resulted in significant T cell proliferation in patients, in response to phytohemagglutinin. Together, these data show that apoptosis mediated by Fas-FasL and engagement of CTLA-4 are involved in modulation of the immune response in patients infected with Paracoccidioides brasiliensis