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-β, 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-β, 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-β+, 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.

Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells

“…T regs have been reported to display higher levels of CCR5, a receptor of CCL5, than effector T cells. CCR5 is responsible for the migration of T regs in murine pancreatic cancer and in fungal infections [35,49]. However, the expression of CCR5 on T regs isolated from ovarian cancer patients was not understood clearly.…”

An overview of the immunopathology of human paracoccidioidomycosis

“…In this regard, Silva and coworkers in an elegant study investigated the role of regulatory TCD4 + CD25 + cells. Such cells, expanded from patients' lesions, either inhibited or stimulated the proliferative capacity of allogeneic PBMC [67,68]. The regulatory T-cells derived from four chronic form patients exhibited an inhibitory capacity, while those form acute/subacute form exhibited either a stimulatory (three patients) or inhibitory (one patient) activity.…”

Polymorphism analysis of the CTLA-4 gene in paracoccidioidomycosis patients

“…Although some studies have been published concerning the influence of CTLA-4 on PCM (Bozzi et al 2004, Cavassani et al 2006, this study is the first to assess the association of polymorphisms and the fungal illness. Notably, population and individual genetic structure analysis was carried out on the patient and control groups.…”

“…There is increased expression of CTLA-4 protein in Treg cells of PCM patients relative to control groups. In addition, Treg cells are present in the lesions and peripheral blood from patients with the chronic form of PCM, suggesting local and systemic regulation of the immune response in this illness (Cavassani et al 2006). This study aimed to verify the association between CTLA-4 gene polymorphisms and the risk of developing PCM.…”

“…Human and experimental PCM evoke a great variety of immune responses with a large range of clinical manifestations, which depend on the degree of suppression of cellular immunity (Bocca et al 1998, Campanelli et al 2003, Cavassani et al 2006). An imbalance in cytokine production, apoptosis-induced cell death and high levels of Fas-L and CTLA-4 expression in T cells seem to be involved in T cell unresponsiveness.…”