CD4+CD25hiFoxp3+ regulatory T-cells (Tregs) are of
crucial importance in regulating the immune response, including the control of any
defense against infection. Their presence in periapical lesions has not been
demonstrated, as yet. We hypothesized that Tregs infiltrate periapical lesions, where
they inhibit T-cell proliferation. The aim of this study was to characterize Tregs in
periapical lesions by confocal microscopy, flow cytometry, and functional assays. We
showed that CD4+CD25hiFoxp3+ cells in periapical
lesions expressed IL-10 and TGF-β. Their frequency was significantly higher than in
peripheral blood and correlated with the levels of TGF-β and IL-10 in culture
supernatants of periapical lesion mononuclear cells. Tregs inhibited the
proliferation of responder T-cells in vitro, at least in part, by
stimulating the production of IL-10. These findings suggest that
CD4+CD25hiFoxp3+ cells in periapical lesions may
play regulatory roles in controlling local immune/inflammatory processes.
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References
1.
Akamine A, Hashiguchi I, Toriya Y, Maeda K
(1994). Immunohistochemical examination on the localization of
macrophages and plasma cells in induced rat periapical lesions. Endod Dent
Traumatol10:121–128.
2.
Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA
(2001). CD4+CD25 high regulatory cells in human peripheral blood.
J Immunol167: 1245–1253.
3.
Cardoso CR, Garlet GP, Moreira AP, Júnior WM, Rossi MA,
Silva JS (2008). Characterization of CD4+CD25+ natural regulatory T
cells in the inflammatory infiltrate of human chronic periodontitis. J Leukoc
Biol84:311–318.
4.
Cavassani KA, Campanelli AP, Moreira AP, Vancim JO, Vitali
LH, Mamede RC, et al. (2006). Systemic and local
characterization of regulatory T cells in a chronic fungal infection in humans.
J Immunol177:5811–5818.
5.
Colić M, Lukić A, Vucević D, Milosavljević P,
Majstorović I, Marjanović M, et al. (2006).
Correlation between phenotypic characteristics of mononuclear cells isolated from
human periapical lesions and their in vitro production of Th1 and Th2 cytokines.
Arch Oral Biol51:1120–1130.
6.
Colić M, Vasilijić S, Gazivoda D, Vucević D,
Marjanović M, Lukić A (2007). Interleukin-17 plays a role in
exacerbation of inflammation within chronic periapical lesions. Eur J Oral
Sci115:315–320.
7.
Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali
KM, et al. (2007). The inhibitory cytokine IL-35
contributes to regulatory T cell function. Nature450:566–569.
8.
Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G
(2002). Human CD4+CD25+ regulatory, contact-dependent T cells induce
interleukin 10-producing, contact-independent type 1-like regulatory T cells.
J Exp Med196:247–253; errata in J Exp
Med 196:559, 2002 and 196: 867, 2002.
9.
Ernst CW, Lee JE, Nakanishi T, Karimbux NY, Rezende TM,
Stashenko P, et al. (2007). Diminished forkhead box
P3/CD25 double-positive T regulatory cells are associated with the increased nuclear
factor-kappaB ligand (RANKL+) T cells in bone resorption lesion of periodontal
disease. Clin Exp Immunol148:271–280.
10.
Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR,
Neurath MF (2004). Cutting edge: TGF-beta induces a regulatory phenotype
in CD4+CD25− T cells through Foxp3 induction and
down-regulation of Smad7. J Immunol172: 5149–5153.
11.
Fehervari Z, Sakaguchi S (2004). CD4+ Tregs
and immune control. J Clin Invest114:1209–1217.
12.
Fukada SY, Silva TA, Garlet GP, Rosa AL, da Silva JS,
Cunha FQ (2009). Factors involved in the T helper type 1 and type 2 cell
commitment and osteoclast regulation in inflammatory apical diseases. Oral
Microbiol Immunol24:25–31.
13.
Guilliams M, Oldenhove G, Noel W, Hérin M, Brys L, Loi P,
et al. (2007). African trypanosomiasis: naturally
occurring regulatory T cells favor trypanotolerance by limiting pathology associated
with sustained type 1 inflammation. J Immunol179: 2748–2757.
14.
Hori S, Nomura T, Sakaguchi S (2003). Control
of regulatory T cell development by the transcription factor Foxp3.
Science299:1057–1061.
15.
Hubert P, Jacobs N, Caberg JH, Boniver J, Delvenne P
(2007). The crosstalk between dendritic and regulatory T cells: good
or evil? J Leukoc Biol82:781–794.
16.
Jonuleit H, Schmitt E, Kakriman H, Stassen M, Knop J, Enk
AH (2002). Infectious tolerance: human CD25+ regulatory T cells convey
suppressor activity to conventional CD4+ T helpercells. J Exp Med196:255–260.
17.
Kawashima N, Stashenko P (1999). Expression
of bone-resorptive and regulatory cytokines in murine periapical inflammation.
Arch Oral Biol44:55–66.
18.
Lukić A (2000). Transforming growth
factor-beta is a major down-regulatory cytokine in periapical lesions. Balkan
Stomatology4:157–160.
19.
Lukić A, Vasilijić S, Majstorović I, Vucević D,
Mojsilović S, Gazivoda D, et al. (2006).
Characterization of antigen-presenting cells in human apical periodontitis lesions by
flow cytometry and immunocytochemistry. Int Endod J39:626–636.
20.
Marie JC, Letterio JJ, Gavin M, Rudensky AY
(2005). TGF-β1 maintains suppressor function and Foxp3 expression in
CD4+CD25+ regulatory T cells. J Exp Med201:1061–1067.
21.
Marton IJ, Kiss C (2000). Protective and
destructive immune reactions in apical periodontitis. Oral Microbiol
Immunol15:139–150.
22.
Mendez S, Reckling SK, Piccirillo CA, Sacks D, Belkaid Y
(2004). Role for CD4(+) CD25(+) regulatory T cells in reactivation of
persistent leishmaniasis and control of concomitant immunity. J Exp
Med200: 201–210.
23.
Nair PN (2004). Pathogenesis of apical
periodontitis and the causes of endodontic failures. Crit Rev Oral Biol
Med15:348–381.
24.
Nakajima T, Ueki-Maruyama K, Oda T, Ohsawa Y, Ito H,
Seymour GJ, et al. (2005). Regulatory T-cells
infiltrate periodontal disease tissues. J Dent Res84:639–643.
25.
Nocentini G, Giunchi L, Ronchetti S, Krausz LT, Bartoli A,
Moraca R, et al. (1997). A new member of the tumor
necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced
apoptosis. Proc Natl Acad Sci USA94:6216–6221.
26.
Prevosto C, Zancolli M, Canevali P, Zocchi MR, Poggi A
(2007). Generation of CD4+ or CD8+ regulatory T
cells upon mesenchymal stem cell-lymphocyte interaction.
Haematologica92:881–888.
27.
Ronchetti S, Zollo O, Bruscoli S, Agostini M, Bianchini R,
Nocentini G, et al. (2004). GITR, a member of the TNF
receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations.
Eur J Immunol34:613–622.
28.
Shevach EM (2002). CD4+ CD25+ suppressor T
cells: more questions than answers. Nat Rev Immunol2:389–400.
29.
Tani N, Osada T, Watanabe Y, Umemoto T
(1992). Comparative immunohistochemical identification and relative
distribution of immunocompetent cells in sections of frozen or formalin-fixed tissue
from human periapical inflammatory lesions. Endod Dent Traumatol8:163–169.
30.
Toda A, Piccirillo CA (2006). Development and
function of naturally occurring CD4+CD25+ regulatory T cells. J Leukoc
Biol80:458–470.
31.
Vignali DA, Collison LW, Workman CJ (2008).
How regulatory T cells work. Nat Rev Immunol8:523–532.
32.
von Boehmer H (2005). Mechanisms of
suppression by suppressor T cells. Nat Immunol6:338–344.
33.
Wallstrom JB, Torabinejad M, Kettering J, McMillan P
(1993). Role of T cells in the pathogenesis of periapical lesions. A
preliminary report. Oral Surg Oral Med Oral Pathol76:213–218.
34.
Waterman PA Jr, Torabinejad M, McMillan PJ, Kettering JD
(1998). Development of periradicular lesions in immunosuppressed
rats. Oral Surg Oral Med Oral Pathol Oral Radiol Endod85:720–725.
35.
Wing K, Suri-Payer E, Rudin A (2005).
CD4+CD25+-regulatory T cells from mouse to man. Scand J Immunol62:1–15.
