title: Systemic and local characterization of regulatory T cells in a chronic fungal infection in humans.
abstract: The long-term persistence of pathogens in a host is a hallmark of certain infectious diseases, including schistosomiasis, leishmaniasis, and paracoccidioidomycosis (PCM). Natural regulatory T (Treg) cells are involved in control of the immune responses, including response to pathogens. Because CTLA-4 is constitutively expressed in Treg cells and it acts as a negative regulator of T cell activation in patients with PCM, here we investigated the involvement of Treg cells in the control of systemic and local immune response in patients with PCM. We found that the leukocyte subsets were similar in patients and controls, except for CD11c+CD1a+ cells. However, a higher frequency of CD4+CD25+ T cells expressing CTLA-4, glucorticoid-inducible TNFR, membrane-bound TGF-beta, and forkhead-box 3 were observed in PBMC of patients. In accordance, these cells exhibited stronger suppressive activity when compared with those from controls (94.0 vs 67.5% of inhibition of allogeneic T cell proliferation). In addition, the data showed that CD4+CD25+ T cells expressing CTLA-4+, glucocorticoid-inducible TNFR positive, CD103+, CD45RO+, membrane-bound TGF-beta, forkhead-box 3 positive, and the chemokines receptors CCR4 and CCR5 accumulate in the Paracoccidioides brasiliensis-induced lesions. Indeed, the secreted CCL17 and CCL22, both associated with the migration of Treg cells to peripheral tissues, were also detected in the biopsies. Moreover, the CD4+CD25+ T cell derived from lesions, most of them TGF-beta+, also exhibited functional activity in vitro. Altogether, these data provide the first evidence that Treg cells play a role in controlling local and systemic immune response in patients with a fungal-induced granulomatous disease advancing our understanding about the immune regulation in human chronic diseases.
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine, Ribeirão Preto-Universidade de São Paulo, Avenida Bandeirantes 3900, 14049-900 Ribeirão Preto, São Paulo, Brazil.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Cavassani
authors.forename: Ana P
authors.initials: AP
authors.lastname: Campanelli
authors.forename: Ana P
authors.initials: AP
authors.lastname: Moreira
authors.forename: Jaqueline O
authors.initials: JO
authors.lastname: Vancim
authors.forename: Lucia H
authors.initials: LH
authors.lastname: Vitali
authors.forename: Rui C
authors.initials: RC
authors.lastname: Mamede
authors.forename: Roberto
authors.initials: R
authors.lastname: Martinez
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D000943:Antigens, Differentiation / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis*; D060908:CTLA-4 Antigen; D002462:Cell Membrane / Q000737:chemistry / Q000276:immunology; D002465:Cell Movement; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D018925:Chemokines / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000032:analysis; D006801:Humans; D039001:Integrin alpha Chains / Q000032:analysis; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis*; D017493:Leukocyte Common Antigens / Q000032:analysis; D010229:Paracoccidioidomycosis / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D054398:Receptors, CCR4; D019713:Receptors, CCR5 / Q000032:analysis; D019707:Receptors, Chemokine / Q000032:analysis; D017475:Receptors, Nerve Growth Factor / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000032:analysis
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; C106230:CCL17 protein, human; C515482:CCL22 protein, human; C515354:CCR4 protein, human; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; C496505:FOXA3 protein, human; D053450:Glucocorticoid-Induced TNFR-Related Protein; D039001:Integrin alpha Chains; D053645:Interleukin-2 Receptor alpha Subunit; D054398:Receptors, CCR4; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C491405:TNFRSF18 protein, human; D016212:Transforming Growth Factor beta; C091367:alpha E integrins; D051543:Hepatocyte Nuclear Factor 3-gamma; D017493:Leukocyte Common Antigens