IL2 is required for functional maturation of regulatory T cells

다국어 초록 (Multilingual Abstract)

Regulatory T cells (Tregs), specified by the expression of transcription factor Foxp3, operate Foxp3- dependent programs to maintain self-tolerance. In addition to Foxp3, other tissue-specific transcription factors are also required by Tregs to control the corresponding immune responses like follicular Tregs which express both Foxp3 and Bcl6 controlling germinal center reactions.
Here, we show that Interleukin 2 (IL2) is required for the optimal expression of T helper type 1 (Th1) transcription factor T-box 21 (Tbx21, T-bet) in Tregs. The expression levels of CXCR3 and Tbet were reduced in IL2 deficient Tregs. Furthermore, IL2 deficient Treg cells failed to control the proliferation of CD4+ T cells in vitro and could not prevent the progression of colitis characterized by Th1 immune responses. Taken together, our data suggest that IL2 is essential for the functional maturation of Tregs including the optimal suppressive activity and the expression of tissue-specific transcription factors like T-bet.

참고문헌 (Reference)

1 Wildin RS, "Xlinked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy" 27 : 18-20, 2001

2 Xavier RJ, "Unravelling the pathogenesis of inflammatory bowel disease" 448 : 427-434, 2007

3 Koch MA, "The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation" 10 : 595-602, 2009

4 Ferlin WG, "The induction of a protective response in Leishmania major-infected BALB/c mice with anti-CD40 mAb" 28 : 525-531, 1998

5 Malek TR, "The biology of interleukin-2" 26 : 453-479, 2008

6 Cheng G, "T-cell tolerance and the multifunctional role of IL-2R signaling in T-regulatory cells" 241 : 63-76, 2011

7 Koch MA, "T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor beta2" 37 : 501-510, 2012

8 Galgani M, "Role of metabolism in the immunobiology of regulatory T cells" 197 : 2567-2575, 2016

9 Zheng Y, "Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses" 458 : 351-356, 2009

10 Wing JB, "Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4" 41 : 1013-1025, 2014

11 Belkaid Y, "Regulatory T cells and infection: a dangerous necessity" 7 : 875-888, 2007

12 Sakaguchi S, "Regulatory T cells and immune tolerance" 133 : 775-787, 2008

13 Rubtsov YP, "Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces" 28 : 546-558, 2008

14 Liao W, "Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alphachain expression" 9 : 1288-1296, 2008

15 Campbell DJ, "Phenotypical and functional specialization of FOXP3+ regulatory T cells" 11 : 119-130, 2011

16 Cipolletta D, "PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells" 486 : 549-553, 2012

17 김기범, "Negative regulation of peroxiredoxin 6 (Prdx 6) transcription by nuclear oncoprotein DEK during leukemia cell differentiation" 한국통합생물학회 18 (18): 318-323, 2014

18 Liao W, "Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages" 12 : 551-559, 2011

19 Malek TR, "Interleukin-2 receptor signaling: at the interface between tolerance and immunity" 33 : 153-165, 2010

20 Newton R, "Immunometabolism of regulatory T cells" 17 : 618-625, 2016

21 Cheng G, "IL-2R signaling is essential for functional maturation of regulatory T cells during thymic development" 190 : 1567-1575, 2013

22 Cao X, "Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance" 27 : 635-646, 2007

23 허지인, "FOXO3a Activation by oxyresveratrol of Morus bombycis koidzumi extract mediates antioxidant activity" 한국통합생물학회 20 (20): 39-47, 2016

24 Brunkow ME, "Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse" 27 : 68-73, 2001

25 Schorle H, "Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting" 352 : 621-624, 1991

26 Mottet C, "Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells" 170 : 3939-3943, 2003

27 Chaudhry A, "CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner" 326 : 986-991, 2009

28 Oestreich KJ, "Bcl-6 directly represses the gene program of the glycolysis pathway" 15 : 957-964, 2014

29 Savage PA, "Basic principles of tumor-associated regulatory T cell biology" 34 : 33-40, 2013

30 최진화, "Anti-tumor Immunity Induced by Tumor Cells Expressing a Membrane-bound Form of IL-2 and SDF-1" 한국통합생물학회 12 (12): 193-201, 2008

31 Fu W, "A multiply redundant genetic switch ‘locks in’ the transcriptional signature of regulatory T cells" 13 : 972-980, 2012

32 Fontenot JD, "A function for interleukin 2 in Foxp3-expressing regulatory T cells" 6 : 1142-1151, 2005

33 Haribhai D, "A central role for induced regulatory T cells in tolerance induction in experimental colitis" 182 : 3461-3468, 2009