Characterization of CD4+CD25+ natural regulatory T cells in the inflammatory infiltrate of human chronic periodontitis

Abstract

Periodontitis is an infectious disease, where putative periodontopathogens trigger chronic inflammatory and immune responses against periodontal structures, in which an unbalanced host response is also determinant to the disease outcome. It is reasonable to assume that patient susceptibility to periodontal tissue destruction could be determined by the balance between the response against periodontopathogens and regulatory mechanisms of these events mediated by suppressive T cells. In the present study, we identified and characterized natural regulatory T cells (Tregs) in the inflammatory infiltrate of human chronic periodontitis (CP) with emphasis on phenotypic analyses that were carried out to address the participation of Tregs in CP. Results showed that patients with CP presented increased frequency of T lymphocytes and CD4+CD25+ T cells in the inflammatory infiltrate of gingival tissues. These cells exhibited the phenotypic markers of Tregs such as forkhead box p3 (Foxp3), CTLA-4, glucocorticoid-inducible TNFR, CD103, and CD45RO and seemed to be attracted to the inflammation site by the chemokines CCL17 and CCL22, as their expression and its receptor CCR4 were increased in CP patients. Moreover, besides the increased detection of Foxp3 mRNA, diseased tissues presented high expression of the regulatory cytokines IL-10 and TGF-beta. In addition, the inflammatory infiltrate in CP biopsies was composed of CD25+Foxp3+ and CD25+TGF-beta+ cells, thus corroborating the hypothesis of the involvement of Tregs in the pathogenesis of CP. Finally, these results indicate that Tregs are found in the chronic lesions and must be involved in the modulation of local immune response in CP patients.

Distinct Roles for CCR4 and CXCR3 in the Recruitment and Positioning of Regulatory T Cells in the Inflamed Human Liver

“…Until this report, CCR4 was not believed to play a role in the recruitment of T cells to the liver, and few effector cells in the liver express CCR4 (39). CCR4 is the receptor for two chemokines CCL17 and CCL22, both of which are secreted by DCs on maturation, and they recruit and retain T regs in contact with DCs in lymph nodes (44,(47)(48)(49)(50)(51). The interaction between T regs and DCs inhibits DC maturation and the expression of costimulatory molecules required for effector T cell activation (52)(53)(54)(55).…”

Infection and inflammatory mechanisms

“…The cytokines produced by Tregs are TGF-b and T-lymphocyte-associated molecule 4 (CTLA-4), which downregulate inflammation. IL-10, TGF-b and CTLA-4 are reported to decrease periodontal disease progression (Cardoso et al 2008).…”

“…Natural Tregs are CD4 and CD25 expressing T cells that specifically regulate the activation, proliferation, and effector function of activated conventional T-cells (Appay et al 2008, Belkaid & Tarbell 2009, Sallusto & Lanzavecchia 2009. Tregs are found in the periodontal disease sites (Nakajima et al 2005, Cardoso et al 2008). The cytokines produced by Tregs are TGF-b and T-lymphocyte-associated molecule 4 (CTLA-4), which downregulate inflammation.…”

Inflammatory Cytokines and the Pathogenesis of Periodontal Disease

“…Histopathological studies indicate that T cells which are the source of many cytokines are the dominant cell type in periodontitis lesions [18,19]. Th cells can be subdivided into lineages on the basis of cytokine profiles, expression of transcription factors and homing receptors which are named as Th1and Th2 lymphocytes.…”