Regulatory T cells represent unique CD4+CD25+ population of T lymphocytes, which are involved in many immunological events. These cells have very important role in maintaining peripheral tolerance, prevention of autoimmune diseases, in immunological respond to infection, particularly by intracellular microorganisms as well as in a process of tumorogenesiz. There are two populations of regulatory T cells: natural regulatory T cells - nTregs and adaptive, inducible regulatory - iTregs. They differ between each other in accordance to the place of creation, in accordance to the specificity of the T cell receptor, as well as the action mechanism. nTregs and the other T cells arise in thymus, which provides specific inductive environment for maturation and immunological education of progenitor cells to imunocompetent T cells. iTregs arise on periphery from the conventional CD4+ T cells after stimulation by antigen under the different conditions. There is number of subpopulations of iTregs and the most important are Tr1 and Th3 cells. Tr1 cells produce big amounts of interleukin 10 (IL-10), and they are called IL-10-secretory regulatory cells, whereas Th3 cells are necessary for maintenance of peripheral tolerance to mucous surfaces, through their dominant cytokine TGF-â (transforming growth factor-â) and they are most widely spread in the mucosa of the digestive tract. Previous researches have shown that regulatory T cells achieve their suppressor activity via inhibitory cytokines, cytolysis, and induction of metabolic disorders and modulation of maturation or function of dendritic cells.
Pandiyan P, Zheng I, Ishihara S, Reed J, Lendaro MJ. CD4+CD25+ Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T-cells. Nat Immunol. 8:1353–62.
2.
Chen Y, Kuchroo VK, Indole J, Hafler DA, Weiner HL. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science. 265:1237–40.
3.
Fukaura H, Kent SC, Pietrusewicz MJ, Khoury SJ, Weiner HL, Hafler DA. Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J Clin Invest. 98:70–7.
4.
Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev. 182:207–14.
5.
Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 27:232–41.
6.
Jankovic D, Kullberg CM, Feng GC, Goldszmid RS, Collazo MC, Wilson M, et al. Conventional T-bet+ Foxp3- Th1 cells are major source of host-protective regulatory IL-10 during intracellular protozoan infection. J Exp Med. 204:273–83.
7.
Trinchieri G. Interleukin-10 production by effector T cells: Th1 cells show self-control. J Exp Med. 204:239–43.
8.
Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 8:523–32.
9.
Vignali DA. How many mechanisms do regulatory T cells need? Eur J Immunol. 38:908–11.
10.
Joetham A, Takada K, Taube C, Miyahara N, Matsubara S, Rha YH, et al. Naturally occurring lung CD4+CD25+ T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta. J Immunol. 178:1433–42.
11.
Xia ZW, Xu LQ, Zhong WW, Wei JJ, Li NL, Shao J, et al. Heme Oxygenase-1 attenuates ovalbumin-induced airway inflammation by up-regulation of Foxp3 T-regulatory cells, interleukin-10, and membrane-bound transforming growth factor-beta1. Am J Pathol. 171:1904–14.
12.
Collison LW, Workman CJ, Kuo TK, Boyd K, Wang Y, Vignali K, et al. The inhibitory cytokine IL-35 contributes to regulatory T cell function. Nature. 450:566–9.
13.
Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, et al. Granzyme B and perforin are important for regulatory T cells-mediated suppression of tumor clearance. Immunity. 27:635–46.
14.
O’Garra A, Vieira P. Th1 cells control themselves by producing interleukin-10. Nat Rev Immunol. 7:425–8.
15.
Trang Q, Bluestone JA. The Foxp3+ regulatory T cells: a jack of all trades, master of regulation. Nat Immunol. 9:239–44.
16.
Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 322:271–5.
17.
Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 4:762–74.
18.
Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature. 420:502–7.
19.
Singh B, Read S, Asseman C, Malmström V, Mottet C, Stephens LA, et al. Control of intestinal inflammation by regulatory T cells. Immunol Rev. 182:190–200.
20.
Lund JM, Hsing L, Pham TT, Rudensky AY. Coordination of early protective immunity to viral infection by regulatory T cells. Science. 320:1220–4.
21.
Netea MG, Sutmuller R, Herman C, Graaf CA, Meer JW, Krieken JH, et al. Toll-like receptor-2 suppressing immunity against Candida albicans through induction of IL-10 and regulatory T cells. J Immunol. 172:3712–8.
22.
Kursar M, Koch M, Mittrucker HW, Nouailles G, Bonhagen K, Kamradt T, et al. Cutting edge: regulatory T-cells prevent efficient clearance of Mycobacterium tuberculosis. J Immunol. 178:2661–5.
23.
Stoop JN, Molen RG, Baan CC, Laan LJ, Kuipers EJ, Kusters JG, et al. Regulatory T-cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology. 41:771–8.
24.
Belkaid Y. Role of regulatory T cells during infections. Eur J Immunol. 38:918–21.
25.
Sakaguchi S. Regulatory T cells: mediating compromises between host and parasite. Nat Immunol. 4:10–1.
26.
Lio CW, Hsieh CS. A two-step process for thymic regulatory T-cell development. Immunity. 28:100–11.
27.
Green DR, Webb DR. Saying the “S” word in public. Immunol Today. 16:1151–64.
28.
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 155:1151–64.
29.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 4:337–42.
30.
Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol. 3:253–7.
31.
Lan RY, Ansari AA, Lian ZX, Gershwin ME. Regulatory T cells: development, function, and role in autoimmunity. Autoimmun Rev. 4:351–63.
32.
Ladi E, Yin Z, Chtanova T, Robey EA. Thymic microenvironments for T-cell differentiation and selection. Nat Immunol. 7:338–43.
33.
Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley JS, et al. Projection of an immunological self-shadow within the thymus by the Aire protein. Science. 298:1395–401.
34.
Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol. 24:571–606.
35.
Hogquist KA, Baldwin TA, Jameson SC. Central tolerance: learning self-control in the thymus. Nat Rev Immunol. 5:772–82.
36.
Liu YJ. A unified theory of central tolerance in the thymus. Trends Immunol. 27:215–21.
37.
Watanabe N, Wang YH, Lee HK, Ito T, Cao W, Liu YJ. Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature. 436:1181–5.
38.
Liston A, Nutsch KM, Farr AG, Lund JM, Rasmussen JP, Koni PA, et al. Differentiation of regulatory Foxp3+ T cells in thymic cortex. Proc Natl Acad Sci USA. 105:11903–8.
39.
Gershon RK, Cohen P, Hencin R, Liebhaber SA. Suppressor T cells. J Immunol. 108:586–90.
40.
Shevach EM. From vanilla to 28 flavors: multiple varieties of T-regulatory cells. Immunity. 25:195–201.
41.
Bacchetta R, Bigler M, Rouleau M, Antonenko S, Vries JE. High levels of interleukin 10 in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J Exp Med. 172:493–502.
42.
Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, Vries JE. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 389:737–42.
43.
Bacchetta R, Waal Malefijt R, Yssel H, Abrams J, Vries JE, Spits H, et al. Host-reactive CD4+ and CD8+ T cell clones isolated from a human chimera produce IL-5, IL-2, IFN-gamma and granulocyte/macrophage-colony-stimulating factor but not IL-4. J Immunol. 144:902–8.
44.
Viera PL, Christensen M, S O ’Neill, EJ B, FJ B, A B, et al. IL-10-secreting regulatory T-cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol. 172:5986–93.
45.
Bacchetta R, Sartirana C, Levings MK, Bordignon C, Narula S, Roncarolo MG. Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines. Eur J Immunol. 32:2237–45.
Boussiotis AV, Tsai YE, Yunis JE, Thim S, Delgado CJ, Dascher CC, et al. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J Clin Invest. 105:1317–25.
48.
Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, Savelkoul HF, et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med. 195:603–16.
49.
Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 212:28–50.
50.
Hawrylowicz CM, O’Garra A. Potential role of interleukin-10 secreting regulatory T-cells in allergy and asthma. Nat Rev Immunol. 5:271–83.
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