title: Fas-Fas ligand (CD95-CD95L) and cytotoxic T lymphocyte antigen-4 engagement mediate T cell unresponsiveness in patients with paracoccidioidomycosis.
abstract: 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-gamma. Moreover, concomitant inhibition of FasL and of CTLA-4, but not of transforming growth factor-beta, 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.
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Campanelli
authors.forename: Gislâine A
authors.initials: GA
authors.lastname: Martins
authors.forename: Janeusa T
authors.initials: JT
authors.lastname: Souto
authors.forename: Marcelo S F
authors.initials: MS
authors.lastname: Pereira
authors.forename: Márcia C
authors.initials: MC
authors.lastname: Livonesi
authors.forename: Roberto
authors.initials: R
authors.lastname: Martinez
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
mesh_terms: D000069594:Abatacept; D000328:Adult; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism*; D017209:Apoptosis; D060908:CTLA-4 Antigen; D002455:Cell Division; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D053222:Fas Ligand Protein; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D018796:Immunoconjugates; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D010228:Paracoccidioides; D010229:Paracoccidioidomycosis / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D019014:fas Receptor; D000069594:Abatacept