Anti-CD25 treatment depletes Treg cells and decreases disease severity in susceptible and resistant mice infected with Paracoccidioides brasiliensis

• Published in: PloS one 2012-11, Vol.7 (11), p.e51071-e51071
• Main Authors: Felonato, Maíra, Pina, Adriana, de Araujo, Eliseu Frank, Loures, Flávio V, Bazan, Silvia B, Feriotti, Cláudia, Calich, Vera L G
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - pharmacology; Antibodies - therapeutic use; Aspergillus fumigatus; B cells; Biology; Candida albicans; CD25 antigen; CD4 antigen; CD8 antigen; Cell Movement - drug effects; Cell number; Comparative analysis; CTLA-4 protein; Cytokines; Dendritic cells; Disease; Disease Resistance - drug effects; Disease Resistance - immunology; Disease Susceptibility; Diseases; Forkhead Transcription Factors - metabolism; Foxp3 protein; Fungal infections; Fungi; Fungicides; Genotype & phenotype; Health aspects; Helper cells; Immunity; Immunity - drug effects; Immunoregulation; Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Infections; Inflammation; Interleukin 10; Interleukin-10 - biosynthesis; Interleukin-2 Receptor alpha Subunit - immunology; Kynurenine - metabolism; Liver; Liver - drug effects; Liver - pathology; Lung - immunology; Lung - microbiology; Lung - pathology; Lungs; Lymphocyte Count; Lymphocyte Depletion; Lymphocytes; Lymphocytes T; Macrophage Activation - drug effects; Macrophages; Medical research; Medical treatment; Medicine; Mice; Mice, Inbred C57BL; Mycosis; Nitric Oxide - metabolism; Paracoccidioides - drug effects; Paracoccidioides - growth & development; Paracoccidioides - physiology; Paracoccidioides brasiliensis; Paracoccidioidomycosis - drug therapy; Paracoccidioidomycosis - immunology; Paracoccidioidomycosis - microbiology; Paracoccidioidomycosis - pathology; Pathology; Phenotype; Pneumonia; Proteins; Rodents; South American blastomycosis; Spleen; T cells; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Transforming Growth Factor beta - biosynthesis; Transforming growth factors; Tryptophan 2,3-dioxygenase
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0051071

Regulatory T (Treg) cells are fundamental in the control of immunity and excessive tissue pathology. In paracoccidioidomycosis, an endemic mycosis of Latin America, the immunoregulatory mechanisms that control the progressive and regressive forms of this infection are poorly known. Due to its modulatory activity on Treg cells, we investigated the effects of anti-CD25 treatment over the course of pulmonary infection in resistant (A/J) and susceptible (B10.A) mice infected with Paracoccidioides brasiliensis. We verified that the resistant A/J mice developed higher numbers and more potent Treg cells than susceptible B10.A mice. Compared to B10.A cells, the CD4(+)CD25(+)Foxp3(+) Treg cells of A/J mice expressed higher levels of CD25, CTLA4, GITR, Foxp3, LAP and intracellular IL-10 and TGF-β. In both resistant and susceptible mice, anti-CD25 treatment decreased the CD4(+)CD25(+)Foxp3(+) Treg cell number, impaired indoleamine 2,3-dioxygenase expression and resulted in decreased fungal loads in the lungs, liver and spleen. In A/J mice, anti-CD25 treatment led to an early increase in T cell immunity, demonstrated by the augmented influx of activated CD4(+) and CD8(+) T cells, macrophages and dendritic cells to the lungs. At a later phase, the mild infection was associated with decreased inflammatory reactions and increased Th1/Th2/Th17 cytokine production. In B10.A mice, anti-CD25 treatment did not alter the inflammatory reactions but increased the fungicidal mechanisms and late secretion of Th1/Th2/Th17 cytokines. Importantly, in both mouse strains, the early depletion of CD25(+) cells resulted in less severe tissue pathology and abolished the enhanced mortality observed in susceptible mice. In conclusion, this study is the first to demonstrate that anti-CD25 treatment is beneficial to the progressive and regressive forms of paracoccidioidomycosis, potentially due to the anti-CD25-mediated reduction of Treg cells, as these cells have suppressive effects on the early T cell response in resistant mice and the clearance mechanisms of fungal cells in susceptible mice.