Regulatory T-cells Infiltrate Periodontal Disease Tissues

Regulatory T-cells Infiltrate Periodontal Disease Tissues
2005

Journal of Dental Research

Š 2005 International and American Associations for Dental Research

T. Nakajima1,2, K. Ueki-Maruyama1,3, T. Oda1,3, Y. Ohsawa1,3, H. Ito1,3, G.J. Seymour4, and K. Yamazaki1,*

1 Periodontology and Immunology, Department of Oral Health and Welfare, Niigata University Faculty of Dentistry, 5274 Gakkocho 2-ban-cho, Niigata 951-8514, Japan;
2 General Dentistry and Clinical Education Unit, Niigata University Medical and Dental Hospital, Niigata, Japan;
3 Division of Periodontology, Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; and
4 Oral Biology and Pathology, School of Dentistry, The University of Queensland, Brisbane, Australia;

* corresponding author, kaz@dent.niigata-u.ac.jp

ABSTRACT

CD4+CD25+ regulatory T (Tr) cells are critical in regulating the immune response and thereby play an important role in the defense against infection and control of autoimmune diseases. Our previous studies demonstrated the involvement of autoimmune responses in periodontitis. The aim of this study was to identify CD4+CD25+ Tr cells in periodontitis tissues and compare them with those in gingivitis tissues. Immunohistological analysis of CD4, CD25, and CTLA-4 and the gene expression analysis of FOXP3, TGF-?1, and IL-10 on gingival biopsies revealed the presence of CD4+CD25+ Tr cells in all tissues. In periodontitis, the percentage of CD4+CD25+ Tr cells increased with increasing proportions of B-cells relative to T-cells. FOXP3, a characteristic marker for CD4+CD25+ Tr cells, TGF-?1 and IL-10 were expressed more highly in periodontitis compared with gingivitis. These findings suggest that CD4+CD25+ Tr cells and possibly other regulatory T-cell populations do exist and may play regulatory roles in periodontal diseases.

KEY WORDS: regulatory T-cell Ô CD25 Ô FOXP3 Ô periodontal disease Ô immunohistochemistry Ô real-time PCR

INTRODUCTION

Although periodontopathic bacteria are the primary etiological agents in periodontal disease, the ultimate determinant of disease progression and clinical outcome is the hostĚs immune response, which involves the generation of cytokines, the recruitment of inflammatory cells, and the activation of osteoclasts (Seymour et al., 1993). Because of elevated cellular and humoral immune responses to collagen type I (Hirsch et al., 1988; Wassenaar et al., 1995) and self-heat-shock protein 60 (HSP60) (Tabeta et al., 2000; Yamazaki et al., 2002), the immune responses to self-antigens have also been considered as one of the pathogenic pathways in periodontal disease. Therefore, it is reasonable to assume that patientsĚ susceptibility to periodontal tissue destruction could be determined, at least in part, by the balance between putative autoimmune responses and regulatory mechanisms.

It is becoming evident that T-cells with a suppressive function, the so-called Îregulatory T (Tr) cellsĚ, represent a crucial element in the regulatory networks that control immune responses and maintain peripheral tolerance (Thompson and Powrie, 2004). CD4+CD25+ Tr cells play a major role in this regulatory process, and, although originally isolated from mice, they have now been reported in humans (Baecher-Allan et al., 2001; Dieckmann et al., 2001). This population has been implicated not only in the inhibition of the spontaneous development of autoimmune diseases, but also in the control of the immune response to infection (McGuirk and Mills, 2002; Lundgren et al., 2003).

CD4+CD25+ Tr cells constitutively express high levels of CD25 and cytotoxic T-lymphocyte-associated antigen (CTLA)-4, and constitute 5Ň15% of the circulating peripheral CD4+ T-cell population. However, because these phenotypic markers are up-regulated upon activation, they are considered to be insufficient to characterize the CD4+CD25+ Tr cells precisely. Recently, FOXP3, the folkhead/winged helix transcription factor, has been identified as a putative master gene characterizing CD4+CD25+ Tr cells (Hori et al., 2003). We have previously shown that T-cells with suppressive activity, possibly CD4+CD25+ Tr cells expressing elevated levels of CD25 and CTLA-4, can be induced by stimulation with Porphyromonas gingivalis antigens in periodontitis patients (Aoyagi et al., 2000). However, whether or not these unique CD4+CD25+ Tr cells migrate into the periodontal tissues is as yet not known.

Therefore, in the present study, by using both phenotypic marker and gene expression analysis, we investigated the infiltration of CD4+CD25+ Tr cells into periodontal lesions, and whether this T-cell population is elevated in periodontitis lesions compared with gingivitis lesions to maintain immune homeostasis

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