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* Department of Biochemistry and Immunology,
Department of Internal Medicine, and
Department of Ophthalmology, Otorhinolaryngology, and Head and Neck Surgery, School of Medicine, Ribeirão Preto-Universidade de São Paulo (USP), Ribeirão Preto, Brazil; and
Department of Biological Sciences, Bauru Dental School-USP, São Paulo, Brazil
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-
, 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-, 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-+, 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.
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1 This work was supported in part by Fundação de Amparo e Pesquisa de São Paulo (FAPESP) and the Millennium Institute for Vaccine Development and Technology, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). K.A.C. and A.P.M. are Ph.D. students with scholarships from CNPq and FAPESP, respectively. J.S.S. is a research fellow of CNPq.
2 Address correspondence and reprint requests to Dr. João S. Silva, Department of Biochemistry and Immunology, School of Medicine, Ribeirão Preto-Universidade de São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, São Paulo, Brazil. E-mail address: jsdsilva{at}fmrp.usp.br
3 Abbreviations used in this paper: PCM, paracoccidioidomycosis; Treg, regulatory T; GITR, glucocorticoid-inducible TNFR; Foxp3, forkhead-box 3; h, human; rh, recombinant human; MFI, mean fluorescence intensity; LAP, latency associated peptide; DC, dendritic cell; SI, stimulation index.
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