Subject: Aspergillus fumigatus suppresses the human cellular immune   http://www.bloodjournal.org/cgi/content/abstract/2004-09-3421v1 Aspergillus fumigatus suppresses the human cellular immune response via gliotoxin-mediated apoptosis of monocytes Marta Stanzani, Enrico Orciuolo, Russell Lewis, Dimitrios P Kontoyiannis, Sergio L Martins, Lisa S St. John, and Krishna V Komanduri* Transplant Immunology Section, Dept. of Blood and Marrow Transplantation, M.D. Anderson Cancer Center, Houston, TX, USA; Institute of Hematology-Seragnoli, University of Bologna, Bologna, Italy Transplant Immunology Section, Dept. of Blood and Marrow Transplantation, M.D. Anderson Cancer Center, Houston, TX, USA; Dept. of Oncology, Transplant and Advances in Medicine, University of Pisa, Pisa, Italy Transplant Immunology Section, Dept. of Blood and Marrow Transplantation, M.D. Anderson Cancer Center, Houston, TX, USA; Dept. of Infectious Diseases Infection Control and Employee Health, M.D. Anderson Cancer Center, Houston, TX, USA Transplant Immunology Section, Dept. of Blood and Marrow Transplantation, M.D. Anderson Cancer Center, Houston, TX, USA; Dept. of Hematology, Fleury-Diagnostic Medical Center, Sao Paulo, Brazil Transplant Immunology Section, Dept. of Blood and Marrow Transplantation, M.D. Anderson Cancer Center, Houston, TX, USA * Corresponding author; email: kkomanduri@mdanderson.org. Aspergillus fumigatus (AF) is a ubiquitous mold and is the most common cause of invasive aspergillosis, an important source of morbidity and mortality in immunocompromised hosts. Using cytokine flow cytometry, we assessed the magnitude of functional CD4+ and CD8+ T cell responses following stimulation with Aspergillus antigens. Relative to those seen with cytomegalovirus (CMV) or superantigen stimulation, responses to Aspergillus antigens were near background levels. Subsequently, we confirmed that gliotoxin, the most abundant mycotoxin produced by AF, was able to suppress functional T cell responses following CMV or SEB stimulation. Additional studies demonstrated that crude AF filtrates and purified gliotoxin inhibited antigen-presenting cell function and induced the preferential death of monocytes, leading to a marked decrease in the monocyte:lymphocyte ratio. Analysis of caspase-3 activation confirmed that gliotoxin preferentially induced apoptosis of monocytes; similar effects were observed in CD83+ monocyte-derived dendritic cells. Importantly, the physiologic effects of gliotoxin in vitro were observed below concentrations recently observed in the serum of patients with invasive aspergillosis. These studies suggest that the production of gliotoxin by AF may constitute an important immunoevasive mechanism that is mediated by direct efffects on antigen-presenting cells and both direct and indirect effects on T cells.