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CCR5-Dependent Regulatory T Cell Migration Mediates Fungal Survival and Severe Immunosuppression¹

Ana Paula Moreira^*, Karen Angelica Cavassani^*, Fabrine Sales Massafera Tristão^*, Ana Paula Campanelli^*,, Roberto Martinez, Marcos Antonio Rossi and João S. Silva^2,*

^* Department of Biochemistry and Immunology, Department Internal Medicine, Department of Pathology, School of Medicine of Ribeirão Preto, and Department of Biological Sciences, Bauru Dental School, Universidade de São Paulo, São Paulo, Brazil

Paracoccidioidomycosis, a debilitating pulmonary mycosis, is caused by the dimorphic fungus Paracoccidioides brasiliensis. The infection results in the formation of granulomas containing viable yeast cells that are the fungal sources for disease reactivation. Because CD4⁺CD25⁺ regulatory T cells (Tregs) are in the lesions of patients with paracoccidioidomycosis, the migration of Treg cells is dependent on the axis chemokine-chemokine receptors, and CCR5 ligands are produced in P. brasiliensis-induced lesions, we investigated the role of CCR5 in the control of the infection. The results showed that CCR5^–/– mice are more efficient in controlling fungal growth and dissemination and exhibited smaller granulomas than wild-type (WT) mice. In the absence of CCR5, the percentage of CD4⁺CD25⁺ T cells expressing Foxp3, glucocorticoid-induced TNFR (GITR), CD103, CD45^low, and CTLA-4 in the granulomas was significantly decreased. Interestingly, P. brasiliensis infection resulted in an absence of T cell proliferation in response to Con A in WT but not CCR5^–/– mice that was abrogated by anti-CTLA-4 mAb and anti-GITR mAb. Moreover, the adoptive transfer of CD4⁺CD25⁺ but not CD4⁺CD25^– T cells from infected WT to infected CCR5^–/– mice resulted in a significant increase in fungal load. Overall, CCR5 is a key receptor for the migration of Treg cells to the site of P. brasiliensis infection, leading to down-modulation of effector immune response and the long-term presence of the fungus in the granulomas. Thus, a tight control of Treg cell migration to the granulomatous lesions could be an important mechanism for avoiding exacerbation and reactivation of the disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by a grant from Fundação de Amparo à Pesquisa do Estado de São Paulo-Fundaçao de Amparo à Pesquisa do Estado de São Paulo and by The Millennium Institute for Vaccine Development and Technology (CNPq-420067/2005-1).

² Address correspondence and reprint requests to Dr. João S. Silva, School of Medicine of Ribeirão Preto, Universidade de São Paulo, Department of Biochemistry and Immunology, Avenue Bandeirantes, 3900, 14049-900 Ribeirão Preto, São Paulo, Brazil. E-mail address: jsdsilva{at}fmrp.usp.br

³ Abbreviations used in this paper: WT, wild type; Treg, regulatory T cell; GITR, glucocorticoid-induced TNF receptor; p.i., postinfection.