The transcription factor Batf3 inhibits the differentiation of regulatory T cells in the periphery

다국어 초록 (Multilingual Abstract)

Naive CD4 T cells activated by antigen-presenting cells (APCs) undergo terminal differentiation in the periphery. Multiple mechanisms determine their fates, that is, whether they differentiate into conventional T (Tconv) cells or regulatory T (Treg) cells.
The key event during Treg generation is expression of the transcription factor Foxp3, which is the lineage-determining regulator for Treg differentiation and function. Here we show that the transcription factor Batf3 acts as a fate-decision factor with respect to Tconv versus Tregs by restraining Treg differentiation. Batf3 was preferentially expressed in effector CD4 T cells but not in Treg cells, and ectopic expression of Batf3 inhibited Foxp3 induction. Batf3-deficient CD4 T cells favorably differentiated into Treg cells in vitro and in colonic lamina propria. Batf3 KO mice also showed enhanced Treg function in gut-associated immune disease models (for example, ovalbumin tolerance and inflammatory bowel disease models). Batf3 bound to the CNS1 region of the Foxp3 locus and reduced expression of the gene. Thus, Batf3 is a transcriptional suppressor of Treg differentiation.

참고문헌 (Reference)

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

2 Sasidharan Nair V, "Vitamin C facilitates demethylation of the Foxp3 enhancer in a Tet-dependent manner" 196 : 2119-2131, 2016

3 Benoist C, "Treg cells, life history, and diversity" 4 : a007021-, 2012

4 Cebula A, "Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota" 497 : 258-262, 2013

5 Neurath MF, "The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn’s disease" 195 : 1129-1143, 2002

6 Ise W, "The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells" 12 : 536-543, 2011

7 Bennett CL, "The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3" 27 : 20-21, 2001

8 Schraml BU, "The AP-1 transcription factor Batf controls T(H)17 differentiation" 460 : 405-409, 2009

9 Ogawa C, "TGF-beta-mediated Foxp3 gene expression is cooperatively regulated by Stat5, Creb, and AP-1 through CNS2" 192 : 475-483, 2014

10 Gottschalk RA, "TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo" 207 : 1701-1711, 2010

11 Moran AE, "T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse" 208 : 1279-1289, 2011

12 Caton AJ, "Strength of TCR signal from self-peptide modulates autoreactive thymocyte deletion and Foxp3(+)Treg-cell formation" 44 : 785-793, 2014

13 Zheng Y, "Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate" 463 : 808-812, 2010

14 Nishio J, "Requirement of full TCR repertoire for regulatory T cells to maintain intestinal homeostasis" 112 : 12770-12775, 2015

15 Iacobelli M, "Repression of IL-2 promoter activity by the novel basic leucine zipper p21SNFT protein" 165 : 860-868, 2000

16 Shin DS, "Regulatory T cells suppress CD4+ T cells through NFAT-dependent transcriptional mechanisms" 15 : 991-999, 2014

17 Rudensky AY, "Regulatory T cells and Foxp3" 241 : 260-268, 2011

18 Abbas AK, "Regulatory T cells : recommendations to simplify the nomenclature" 14 : 307-308, 2013

19 Xu L, "Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I" 33 : 313-325, 2010

20 Powrie F, "Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice" 5 : 1461-1471, 1993

21 Lathrop SK, "Peripheral education of the immune system by colonic commensal microbiota" 478 : 250-254, 2011

22 Edelson BT, "Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells" 207 : 823-836, 2010

23 Mantel PY, "Molecular mechanisms underlying FOXP3 induction in human T cells" 176 : 3593-3602, 2006

24 Chatila TA, "JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome" 106 : R75-R81, 2000

25 Hadis U, "Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria" 34 : 237-246, 2011

26 de la Rosa M, "Interleukin-2 is essential for CD4+CD25+ regulatory T cell function" 34 : 2480-2488, 2004

27 Yang S, "Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance" 348 : 589-594, 2015

28 Meher PK, "Identification of species based on DNA barcode using k-mer feature vector and Random forest classifier" 592 : 316-324, 2016

29 Li X, "Function of a Foxp3cis-element in protecting regulatory T cell identity" 158 : 734-748, 2014

30 Fontenot JD, "Foxp3 programs the development and function of CD4+CD25+ regulatory T cells" 4 : 330-336, 2003

31 Samstein RM, "Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict" 150 : 29-38, 2012

32 Floess S, "Epigenetic control of the foxp3 locus in regulatory T cells" 5 : e38-, 2007

33 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

34 Ohkura N, "Development and maintenance of regulatory T cells" 38 : 414-423, 2013

35 Tanoue T, "Development and maintenance of intestinal regulatory T cells" 16 : 295-309, 2016

36 Leventhal DS, "Dendritic cells coordinate the development and homeostasis of organ-specific regulatory T cells" 44 : 847-859, 2016

37 Bower KE, "Correlation of transcriptional repression by p21(SNFT) with changes in DNA.NF-AT complex interactions" 277 : 34967-34977, 2002

38 Hori S, "Control of regulatory T cell development by the transcription factor Foxp3" 299 : 1057-1061, 2003

39 Yue X, "Control of Foxp3 stability through modulation of TET activity" 213 : 377-397, 2016

40 Hildner K, "Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity" 322 : 1097-1100, 2008

41 Betz BC, "Batf coordinates multiple aspects of B and T cell function required for normal antibody responses" 207 : 933-942, 2010

42 Kuwahara M, "Bach2-Batf interactions control Th2-type immune response by regulating the IL-4 amplification loop" 7 : 12596-, 2016

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

44 Coombes JL, "A functionally specialized population of mucosal CD103+DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic aciddependent mechanism" 204 : 1757-1764, 2007