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研究生:劉嘉宜
研究生(外文):Ka-Yi Lau
論文名稱:研究誘發Treg-of-B細胞和其抑制活性的機制
論文名稱(外文):Study on the molecular mechanisms of induction and suppressive activity of Treg-of-B cells
指導教授:江伯倫江伯倫引用關係
指導教授(外文):Bor-Luen Chiang
口試委員:繆希椿莊雅惠
口試委員(外文):Shi-Chuen MiawYa-Hui Chuang
口試日期:2015-06-16
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:免疫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:129
中文關鍵詞:B-2 細胞調節性 T 細胞共激分子磷酸化 STAT 蛋白免疫調節
外文關鍵詞:B-2 cellsregulatory T cellsco-stimulatory moleculespStatsimmune regulation
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過去研究指出,B 細胞在免疫系統上能扮演相向調控的角色。而近年來也不斷有文獻指出傳統B-2 細胞能有效提呈抗原給T細胞,並與CD4+CD25- T細胞共同培養之下,B-2細胞能活化以及誘導T細胞成為調節性T細胞,名為Treg-of-B2細胞,以達致免疫調控之效。該調節性T細胞的生成已經證實需要透過CD4+CD25- T細胞和B-2細胞之間的相互接觸,但誘發Treg-of-B2細胞和其抑制活性的機制仍有待釐清。已知活化T細胞需要透過T細胞上的T-細胞受器和抗原提呈细胞上的主要組織相容抗原決定位結合,另外T細胞表面上的共激分子與抗原提呈细胞表面上相應體的結合,則促使T 細胞進一步的活化。再者,細胞因子對於T細胞分化、成熟和功能上扮演著不可決少的角色,它能指導CD4+CD25- T 細胞成為不同的亞群:輔助性細胞或調節性細胞,而細胞因子信號是經由Janus激酶和信號轉導及轉錄激活(STAT)蛋白傳遞的。故本研究欲透過在B-2與CD4+CD25- T細胞共同培養之下,B-2細胞呈現抗體予CD4+CD25- T 細胞時,探討阻斷T細胞表面上的共激分子與B-2細胞表面上相應體的結合會否影響Treg-of-B2的生成。此外,在B-2細胞活化以及誘導CD4+CD25- T細胞成為調節性T細胞的生成過程中和其抑制免疫反應時所受到細胞因子信號以致磷酸化STAT蛋白也一併探究。
於卵蛋白胜肽片段(OVA323-339) 加上抗原呈現細胞的抗原特異性刺激系統下,我們首先從BALB/c 老鼠的脾臟將B-2 細胞分離出來,以OVA323-339加以刺激一天,再與從DO11.10 老鼠的脾臟分離出來的CD4+CD25- T 細胞共同培養三天。三天後重新分離B-2 細胞所誘導出來的CD4+CD25- T 細胞並分析其是否具有抑制能力和調節免疫特性。我們利用不同的中和抗體去阻斷CD4+CD25- T細胞表面上的共激分子與B-2細胞表面上相應體的結合,以利探討單一的共刺激信號阻断在Treg-of-B2細胞生成上的作用。另外,在探討誘發Treg-of-B2生成的過程和其抑制活性中所參與的磷酸化STAT蛋白方面,我們首先從BALB/c 老鼠的脾臟分離B-2 細胞和CD4+ CD25- T 細胞出來並在anti-CD3/CD28單株抗體刺激系統下共同培養三天。在誘發Treg-of-B2細胞生成的三天過程中,我們在特定的時間點收集Treg-of-B2細胞的細胞裂解物,以西方墨點法分析參與的磷酸化STAT蛋白。而在了解其抑制活性中所參與的磷酸化STAT蛋白方面,Treg-of-B2細胞經過三天培養後並分離出來作再度刺激,於不同的特定時間收集經過在anti-CD3/CD28單株抗體再度刺激下Treg-of-B2細胞的細胞裂解物,同樣地以西方墨點法分析參與的磷酸化STAT蛋白。
我們發現於卵蛋白胜肽片段 (OVA323-339) 抗原特異性刺激系統下,B-2細胞能成功的誘導CD4+ CD25- T 細胞為成為調節性T細胞,而該調節性T細胞 (Treg-of-B2細胞)會表現GITR、ICOS、PDL-1和LAG3並且會分泌大量的介白素-10,低量的介白素-4和γ干擾素。 另外我們證明了B-2細胞在作為抗原呈現細胞時,會表現與其他調節性T細胞生成有關的共激分子: GITRL、ICAM-1、ICOSL、CD70 和 OX40L。在單株中和抗體(anti-ICOSL, anti-ICAM-1, anti-CD70, anti-GITRL 或anti-OX40L)下,阻斷CD4+CD25- T細胞表面上的共激分子與B-2細胞表面上相應體的結合,沒能顯著地影響其生成、細胞因子的分泌以及其調節免疫效能。而我們發現在單株中和抗體 (anti-GITRL) 下生成的Treg-of-B2細胞上的GITR表達水平有明顯的下降。另一方面,在anti-CD3/CD28單株抗體刺激系統下,我們證實了在Treg-of-B2細胞生成過程中以及在其發揮抑制活性中參與的磷酸化STAT蛋白有:pStat1、pStat3、pStat5和pStat6,當中以pStat6最為顯著。
本篇的實驗結果支持了B-2細胞可以藉由誘導CD4+ CD25- T 細胞為成為調節性T細胞,以達負向調控免疫反應作用。我們首先證明了Treg-of-B2細胞並非藉由單一的共激通路去誘導CD4+CD25- T細胞成為具有抑制活性的細胞。更進一步分析,在單株中和抗體 (anti-GITRL) 下,以阻斷CD4+CD25- T細胞表面上的GITR與B-2細胞表面上GITRL的結合產生的共激信號,而生成的Treg-of-B2細胞上的GITR表達水平有明顯的下降,但因在單株中和抗體下生成的Treg-of-B2細胞仍俱有調節性功能,故推斷Treg-of-B2的GITR表達水平並沒有參與於負向調控免疫反應作用上。另一方面,Treg-of-B2細胞生成過程中以及在其發揮抑制活性中參與的磷酸化STAT蛋白有:pStat1、pStat3、pStat5和pStat6,當中以pStat6最為顯著。這研究結果使我們得知B-2細胞所誘導出的是一群獨特的調節性細胞亞群,因為它參與的磷酸化STAT蛋白有別於自然產生的調節性T細胞和其他經不同方法誘導而成的調節性T細胞。


B cells are capable to induce immunologic tolerance despite their primary role in humoral immunity. Accumulating evidence with a particular focus on defining conventional B-2 cells can serve as antigen presenting cells to convert naïve CD4+CD25- T cells into regulatory T cells (so-called Treg-of-B cells) in vitro. The B cells primed regulatory T were found to exert a suppressive function on T-cell proliferation. Previous study has already revealed that the mechanism involved in the generation of Treg-of-B cells was in a contact-dependent manner. There was a reversal of suppressive function of Tregs when B cells cultured with T cells were separated by a trans-well membrane. According to the two-signal model of T-cell activation, activation of naïve antigen-specific CD4+ T cells is thought to require at least both stimulation of the T cell receptor (TCR) (Signal 1), and stimulation of costimulatory molecules (Signal 2). The cytokine signal (Signal 3) is additional signal which plays critical role for generating a robust and specialized T-cell response. Many cytokine signaling is transmitted via Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway. In this study, we aim to (1) investigate whether costimulatory blockade by single blocking antibody could boost or dampen Treg-of-B-cell activation and (2) identify the phosphorylated STAT proteins which are involved in induction and suppressive function of Treg-of-B cells.
To induce regulatory T cells stimulated by B-2 cells, naïve B cells were isolated from splenoctyes of BALB/c mice and then pulsed with OVA-peptide for a day. After that, OVA peptide-loaded B cells were co-cultured with naïve CD4+ T cells isolated from splenocytes of DO11.10 mice for 3 days without addition of exogenous cytokines. After a 3 day co-culture, CD4+ T cells were purified after depletion of B220+ cells. The suppressive function of isolated CD4+ T cells was further examined. The effect of costimulatory blockade on B cells generated regulatory T cell was examined by using single neutralizing blocking antibody. On the other hand, to study the involvement of phosphorylated STAT proteins during induction and suppressive function of Treg-of-B cells, naïve B cells were co-cultured with naïve CD4+ T cells which both isolated from splenocytes of BALB/c mice under the stimulation of anti-CD3/CD28 for 3 days. The cell lysates of CD4+ T cells and re-stimulated CD4+ T cells were harvested after depletion of B220+ cells during induction and suppressive function at various time points respectively.
We found that OVA-peptide loaded B-2 cells can serve as antigen presenting cells to induce CD4+ T cells into regulatory T cells (Treg-of-B cells). We further demonstrated that B-2 cells expressed GITRL, ICAM-1, ICOSL, CD70 and OX40L as antigen presenting cells to CD4+ T cells. However, there was no reversal or enhancement of suppressive function of Treg-of-B cells on T-cell proliferation under the treatment of particular single blocking antibody during induction. Only under anti-GITR, the expression of GITR on Treg-of-B cells was significantly down-regulated. On the other hand, we identified that the phosphorylated Stat1, Stat3, Stat5 and Stat6 were involved in the induction and suppressive function of Treg-of-B cells.
Our results confirmed that conventional B-2 cells can modulate immune responses through priming T cells into regulatory T cells. Also, we demonstrated that B cells generated regulatory T cells was not through single costimulatory pathways. We further demonstrated that the expression of GITR on Treg-of-B cells was not a critical molecule to exert suppressive function on T-cell proliferation. On the other hand, we have shown that phosphorylated Stat1, Stat3, Stat5 and Stat6 were involved in the induction and suppressive activity of Treg-of-B cells which is different from nTregs and other inducible Tregs. These findings might help us on identifying Treg-of-B cells into distinct subsets of Treg cells.


Abstract in Chinese……………..………………………………………………………..I
Abstract………………………………………………………………………………...IV
Contents……………...………………………………………………………………..VII
List of figures………………………………………………………………………...XIV

Part I. Study on the effect of costimulatory blockade on induction of Regulatory T cells induced by B cells……………………………………..…………………………..1
Chapter I. Introduction……………………………………………....………………...2
Part. 1 Background…………………………………………………………………3
1. B cell subsets…………………….………………………………………….….3
1. Characterization of B-2 cells………………………………………………3
2. The role of B cells as antigen presenting cells to CD4+ T cells………………...5
1. B cells regulate T cell maturation via serving antigen presenting cells……6
2. B cells regulate T cell activation and effector function via costimulatory receptor/ ligands……………..…………………………………………….7
3. B cells regulate T cell function via secreting cytokine…………………….8
3. Regulatory T cells……………………………………………………………..10
1. Naturally occurring regulatory T cells……………………………………11
2. Inducible regulatory T cells………………………………..……………..12
3.2.1 Type 1 regulatory T cells………………………...………………..13
3.2.1.1 The induction of Type 1 regulatory cells and Tr1-like cells……………………………………………………......14
4. Costimulatory molecules and the development of Tregs……..........................15
1. The role of CD28:CD80/CD86 pathway on Tregs development……..….15
2. The role of LFA-1:ICAM-1 pathway on Tregs development…………….16
3. The role of CD70:CD27 pathway on Tregs development………………..16
4. The role of OX40:OX40L pathway on Tregs development.......................17
5. The role of ICOS:ICOSL pathway on Tregs development……………….18
5. Conventional B-2 cells and the induction of regulatory T cells………………18
Part.2 Specific aim………………………………………………………………...20
Chapter II. Materials and Methods………………………………………………….21
Part. 1 Materials……………………………………………………….…………..22
1. Animals………………………………………………………………………..22
2. Cell culture………………………………………………………....................22
2.1 Culture medium and buffers………………………………………….…...22
2.2 Antigens, mitogens and monoclonal antibodies used in cell culture……..23
3. Flow cytometry………………………………………………………………...24
4. Enzyme-linked immunosorbent ……………………………………………….25
5. MACS cell purification……………………………………………………...…26
6. Proliferation assay……………………………………………………………...26
Part. 2 Methods……………………………………………………………………28
1. Cell culture…………………………………………………………………....28
1.1 Preparation of splenocytes………………………………………………..28
1.2 General cell culture process………………………………………………28
2. Cell isolation…………………………………………………………………..28
3. Induction of Treg cells by B-2 cells…………………………………………...29
4. In vitro Suppression assay…………………………………………………….29
5. Flow cytometric assay…………………………………………….…………..30
6. Cytokine assay………………………………………………….……………..30
7. Statistical analysis……………………………………………………………..32

Chapter III. Results………………………………………………………………...…33
1. Isolation of B-2 and CD4+CD25- T cells……………………………………...34
2. In vitro generation of regulatory T cells induced by B-2 cells under antigen-specific stimulation…………………………………………………...34
3. The suppressive capability of Treg-of-B2 cells in antigen-specific stimulation……………………………………………………………….……35
4. Cell surface marker expression of Treg-of-B2 cells…………………….…....36
5. Cytokine prolife of Treg-of-B2 cells………………………………….………37
6. The costimulatory molecules related to induction of regulatory T cells on B cells……………………………………………………………….…….……..37
7. In vitro generation of regulatory T cells induced by B-2 cells in the presence of single blocking antibody…………………………………………..………….38
8. The suppressive function of regulatory T cells induced by B-2 cell generated in the presence of specific single neutralizing blocking antibody……………….39
9. Cell surface marker expression of Treg-of-B2 cells generated in the presence of specific blocking antibody………………………………………………….....39
10. Cytokine prolife of Treg-of-B2 cells generated in the presence of specific blocking antibody.…………………………………………………………….40
Chapter IV. Discussion………………………………………………………………..42

Part II. Study on the involvement of phosphorylated Stats in the induction and suppressive function of Treg-of-B cells………………………………………………51
Chapter I. Introduction…………………………………………..…………………..52
Part 1. Background………………………………………………………………..53
1. Three signals for CD4+ T-cell activation……………………………………...53
2. Cytokine transmitting signaling and CD4+ T-cell differentiation……………..54
3. STATs………………………………………………………………………….55
4. STATs and Tregs………………………………………………………………56
Part 2. Specific aim………………………………………………………………..58
Chapter II. Materials and Methods………………………………………………….59
Part 1. Materials……………………………………………………………….…..60
1. Animals…………………………………………………..……………………60
2. Cell culture…………………………………………………………………....60
2.1 Culture medium and buffers……………………………………………....60
2.2 Mitogens, monoclonal antibodies and inhibitors used in cell culture…….61
3. Flow cytometry and intracellular staining…………………………………….61
4. Western Blot…………………………………………………………………..62
4.1 Gels and buffers…………………………………………………………..62
4.2 Antibody…………………………………………………………………..63
5. MACS cell purification…………………………………………………….…64
6. Proliferation assay…………………………………………………………….64
Part 2. Methods……………………………………………………………………66
1. Cell culture………………………………………………………………...….66
1.1 Preparation of splencoytes………………………………………………...66
1.2 General cell culture process…………………………………………….…66
2. Cell isolation…………………………………………………………………..66
3. Induction of Treg cells by B-2 cells…………………………………………...67
4. Re-stimulation of Treg-of-B2 cells……………………………………………67
5. Western blot
5.1 Protein extraction………………………………………………………….68
5.2 BCA assay…………………………………………………………………68
5.3 Gel electrophoresis………………………………………………………..69
5.4 Transfer and blocking……………………………………………………..69
5.5 Detection and stripping……………………………………………………69
6. Flow cytometric assay………………………………………………………...70
7. Intracellular staining…………………………………………………………..71
8. In vitro proliferation assay…………………………………………………….72
9. Statistical analysis……………………………………………………………..72
Chapter III. Results………………………………….………………………………..73
1. In vitro generation of regulatory T cells induced by B cells under the stimulation of anti-CD3/CD28………………………...............................74
2. The phosphorylated Stats involved in the induction of Treg-of-B cells….74
3. The Stat6 of CD4+ CD25- T cells from BALB/c or DO11.10 mice were being phosphorylated during the induction of Treg-of-B cells…………...75
4. The inhibitory effect of sodium salicylate (NaSal) on phosphorylation of Stat6 in CD4+CD25- T cells………………………………………………75
5. The effect of sodium salicylate (NaSal) on activation of CD4+ T cells….76
6. The effect of sodium salicylate (NaSal) on proliferation ability of CD4+ T cells…...…………………………………………………………………..76
7. The phosphorylated STATs involved in the induction of Treg-of-B cells..77

Chapter IV. Discussion………………………………………………………………..78
Figures………………………………………………………………………………….83
References...…...………………………………………………………………………114

List of Figures
Figure 1. Purification of B-2 and CD4+CD25− Teff cells by BD IMagTM system…….84
Figure 2. Schemes of Regulatory T cells induction by B-2 cells under antigen-specific stimulation………………..…………………………………………………………….85
Figure 3. The regulatory capability of Treg-of-B2 on responder Teff cells under antigen-specific stimulation…………………………………………………………….86
Figure 4. The extent of suppression was dependent on the Treg-of-B: Teff ratio under antigen-specific stimulation…………………………………………………………….87
Figure 5. Cell surface markers of Treg-of-B2 cells……………………...……………..88
Figure 6. Cytokine profile of Treg-of-B2 cells…………………………………..…….90
Figure 7. Costimulatory molecules of B cells in different states………..……………..91
Figure 8. Representative flow cytometric analysis of costimulatory molecules on B cells in different states………………………………………………..………………………93
Figure 9. Schemes of Treg-of-B2 cell under antigen-specific stimulation and specific blocking antibody……………………………………………………….……………...96
Figure 10. The regulatory capacity of Treg-of-B2 cell under antigen-specific stimulation and specific blocking antibody…………………………………………………………97
Figure 11. Cytokine prolife of Treg-of-B2 cells generated in the presence of specific blocking antibody………………………………………………………………………99
Figure 12. Characteristics of Treg-of-B2 cells generated in the presence of specific blocking antibody………………………………………...…………………………...101
Figure 13. Scheme of B cells serve as antigen presenting to convert CD4+ T cells into regulatory T cells in the presence of single blocking antibody…………………….…103
Figure 14. Schemes of Treg-of-B2 cell under the stimulation of anti-CD3/CD28……105
Figure 15. Western Blot for detecting phosphorylated Stats of Treg-of-B2 cells which are involved in induction of Treg-of-B cells………………….………………………106
Figure 16. Intracellular staining for analyzing phosphorylated Stat6 of Treg-of-B cells during induction……………………………………………………………………….107
Figure 17. Intracellular staining for analyzing phosphorylated Stat6 of T cells stimulated with IL-4 under the treatment of Sodium Salicylate (NaSal)…………………………109
Figure 18. Activation marker of CD4+CD25- T cell after treatment of Sodium Salicylate (NaSal)………………………………………………………………………………...110
Figure 19. The proliferation of CD4+CD25- T cell after treatment of Sodium Salicylate (NaSal)…...……………………………………………………………………………111
Figure 20. Western Blot for detecting phosphorylated STATs of Treg-of-B2 cells which are involved in suppressive function of Treg-of-B cells……………………………....112
Figure 21. Scheme of activated Stats during the induction and suppressive function of Treg-of-B cells………………………………………………………………………...113



Reference:
1.Allman D, Pillai S. Peripheral B cell subsets. Current Opinion in Immunology 2008, 20(2): 149-157.

2.LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood 2008, 112(5): 1570-1580.

3.Sindhava VJ, Bondada S. Multiple regulatory mechanisms control B-1 B cell activation. Frontiers in Immunology 2012, 3: 372.

4.Hardy RR, Hayakawa K. B cell development pathways. Annual Review of Immunology 2001, 19: 595-621.

5.Kantor AB, Herzenberg LA. Origin of murine B cell lineages. Annual Review of Immunology 1993, 11: 501-538.

6.Montecino-Rodriguez E, Dorshkind K. B-1 B cell development in the fetus and adult. Immunity 2012, 36(1): 13-21.

7.Parker DC. T cell-dependent B cell activation. Annual Review of Immunology 1993, 11: 331-360.

8.Shapiro-Shelef M, Lin KI, Savitsky D, Liao J, Calame K. Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow. The Journal of Experimental Medicine 2005, 202(11): 1471-1476.

9.Chen X, Jensen PE. The role of B lymphocytes as antigen-presenting cells. Archivum Immunologiae et Therapiae Experimentalis 2008, 56(2): 77-83.

10.Yang M, Rui K, Wang S, Lu L. Regulatory B cells in autoimmune diseases. Cellular & Molecular Immunology 2013, 10(2): 122-132.

11.Ugrinovic S, Menager N, Goh N, Mastroeni P. Characterization and development of T-Cell immune responses in B-cell-deficient (Igh-6(-/-)) mice with Salmonella enterica serovar Typhimurium infection. Infection and Immunity 2003, 71(12): 6808-6819.

12.Moseman EA, Iannacone M, Bosurgi L, Tonti E, Chevrier N, Tumanov A, et al. B cell maintenance of subcapsular sinus macrophages protects against a fatal viral infection independent of adaptive immunity. Immunity 2012, 36(3): 415-426.

13.Buendia AJ, Del Rio L, Ortega N, Sanchez J, Gallego MC, Caro MR, et al. B-cell-deficient mice show an exacerbated inflammatory response in a model of Chlamydophila abortus infection. Infection and Immunity 2002, 70(12): 6911-6918.

14.Ron Y, Sprent J. T cell priming in vivo: a major role for B cells in presenting antigen to T cells in lymph nodes. Journal of Immunology 1987, 138(9): 2848-2856.

15.Reichardt P, Dornbach B, Rong S, Beissert S, Gueler F, Loser K, et al. Naive B cells generate regulatory T cells in the presence of a mature immunologic synapse. Blood 2007, 110(5): 1519-1529.

16.Malynn BA, Romeo DT, Wortis HH. Antigen-specific B cells efficiently present low doses of antigen for induction of T cell proliferation. Journal of Immunology 1985, 135(2): 980-988.

17.Rivera A, Chen CC, Ron N, Dougherty JP, Ron Y. Role of B cells as antigen-presenting cells in vivo revisited: antigen-specific B cells are essential for T cell expansion in lymph nodes and for systemic T cell responses to low antigen concentrations. International Immunology 2001, 13(12): 1583-1593.

18.Rodriguez-Pinto D. B cells as antigen presenting cells. Cellular Immunology 2005, 238(2): 67-75.

19.Eynon EE, Parker DC. Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. The Journal of Experimental Medicine 1992, 175(1): 131-138.

20.Bretscher P, Cohn M. A theory of self-nonself discrimination. Science 1970, 169(3950): 1042-1049.

21.Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nature Reviews Immunology 2001, 1(3): 220-228.

22.Guerder S, Flavell RA. T-cell activation. Two for T. Current Biology : CB 1995, 5(8): 866-868.

23.Zheng J, Liu Y, Lau YL, Tu W. CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD4(+) regulatory T cells. Cellular & Molecular Immunology 2010, 7(1): 44-50.

24.O''Neill SK, Cao Y, Hamel KM, Doodes PD, Hutas G, Finnegan A. Expression of CD80/86 on B cells is essential for autoreactive T cell activation and the development of arthritis. Journal of Immunology 2007, 179(8): 5109-5116.

25.Kalampokis I, Yoshizaki A, Tedder TF. IL-10-producing regulatory B cells (B10 cells) in autoimmune disease. Arthritis Research & Therapy 2013, 15 Suppl 1: S1.

26.Zheng J, Liu Y, Qin G, Lam KT, Guan J, Xiang Z, et al. Generation of human Th1-like regulatory CD4+ T cells by an intrinsic IFN-gamma- and T-bet-dependent pathway. European Journal of Immunology 2011, 41(1): 128-139.

27.Lund FE. Cytokine-producing B lymphocytes-key regulators of immunity. Current Opinion in Immunology 2008, 20(3): 332-338.

28.Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nature Reviews Immunology 2010, 10(4): 236-247.

29.Amu S, Saunders SP, Kronenberg M, Mangan NE, Atzberger A, Fallon PG. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model. The Journal of Allergy and Clinical Immunology 2010, 125(5): 1114-1124 e1118.

30.Shen P, Roch T, Lampropoulou V, O''Connor RA, Stervbo U, Hilgenberg E, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 2014, 507(7492): 366-370.

31.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. Journal of Immunology 1995, 155(3): 1151-1164.

32.Chatenoud L. Natural and induced T CD4+CD25+FOXP3+ regulatory T cells. Methods in Molecular Biology 2011, 677: 3-13.

33.Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nature Reviews Immunology 2003, 3(3): 253-257.

34.Jonuleit H, Schmitt E. The regulatory T cell family: distinct subsets and their interrelations. Journal of Immunology 2003, 171(12): 6323-6327.

35.Collison LW, Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J, et al. IL-35-mediated induction of a potent regulatory T cell population. Nature Immunology 2010, 11(12): 1093-1101.

36.Dons EM, Raimondi G, Cooper DK, Thomson AW. Induced regulatory T cells: mechanisms of conversion and suppressive potential. Human Immunology 2012, 73(4): 328-334.

37.Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. The Journal of Experimental Medicine 2012, 209(10): 1713-1722, S1711-1719.

38.Lin X, Chen M, Liu Y, Guo Z, He X, Brand D, et al. Advances in distinguishing natural from induced Foxp3(+) regulatory T cells. International Journal of Clinical and Experimental Pathology 2013, 6(2): 116-123.

39.Venturi GM, Conway RM, Steeber DA, Tedder TF. CD25+CD4+ regulatory T cell migration requires L-selectin expression: L-selectin transcriptional regulation balances constitutive receptor turnover. Journal of Immunology 2007, 178(1): 291-300.

40.Shevach EM. CD4+ CD25+ suppressor T cells: more questions than answers. Nature Reviews Immunology 2002, 2(6): 389-400.

41.Seddiki N, Santner-Nanan B, Tangye SG, Alexander SI, Solomon M, Lee S, et al. Persistence of naive CD45RA+ regulatory T cells in adult life. Blood 2006, 107(7): 2830-2838.

42.Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. Journal of Immunology 2000, 164(1): 183-190.

43.Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunological Reviews 2001, 182: 18-32.

44.Malek TR, Yu A, Vincek V, Scibelli P, Kong L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 2002, 17(2): 167-178.

45.Lio CW, Hsieh CS. A two-step process for thymic regulatory T cell development. Immunity 2008, 28(1): 100-111.

46.Workman CJ, Szymczak-Workman AL, Collison LW, Pillai MR, Vignali DA. The development and function of regulatory T cells. Cellular and Molecular Life Sciences : CMLS 2009, 66(16): 2603-2622.

47.Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 2009, 30(5): 626-635.

48.Groux H, O''Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997, 389(6652): 737-742.

49.Vieira PL, Christensen JR, Minaee S, O''Neill EJ, Barrat FJ, Boonstra A, 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. Journal of Immunology 2004, 172(10): 5986-5993.

50.Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunological Reviews 2001, 182: 207-214.

51.Skapenko A, Kalden JR, Lipsky PE, Schulze-Koops H. The IL-4 receptor alpha-chain-binding cytokines, IL-4 and IL-13, induce forkhead box P3-expressing CD25+CD4+ regulatory T cells from CD25-CD4+ precursors. Journal of Immunology 2005, 175(9): 6107-6116.

52.Pot C, Apetoh L, Awasthi A, Kuchroo VK. Induction of regulatory Tr1 cells and inhibition of T(H)17 cells by IL-27. Seminars in Immunology 2011, 23(6): 438-445.

53.Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biology 2007, 5(2): e38.

54.Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. The Journal of Experimental Medicine 2007, 204(8): 1765-1774.

55.Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunological Reviews 2006, 212: 28-50.

56.Palomares O, Yaman G, Azkur AK, Akkoc T, Akdis M, Akdis CA. Role of Treg in immune regulation of allergic diseases. European Journal of Immunology 2010, 40(5): 1232-1240.

57.Battaglia M, Gianfrani C, Gregori S, Roncarolo MG. IL-10-producing T regulatory type 1 cells and oral tolerance. Annals of the New York Academy of Sciences 2004, 1029: 142-153.

58.Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG. Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood 2005, 105(3): 1162-1169.

59.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. European Journal of Immunology 2002, 32(8): 2237-2245.

60.Roncarolo MG, Levings MK, Traversari C. Differentiation of T regulatory cells by immature dendritic cells. The Journal of Experimental Medicine 2001, 193(2): F5-9.

61.Groux H, Bigler M, de Vries JE, Roncarolo MG. Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. The Journal of Experimental Medicine 1996, 184(1): 19-29.

62.Fu CL, Chuang YH, Huang HY, Chiang BL. Induction of IL-10 producing CD4+ T cells with regulatory activities by stimulation with IL-10 gene-modified bone marrow derived dendritic cells. Clinical and Eexperimental Immunology 2008, 153(2): 258-268.

63.Ahangarani RR, Janssens W, VanderElst L, Carlier V, VandenDriessche T, Chuah M, et al. In vivo induction of type 1-like regulatory T cells using genetically modified B cells confers long-term IL-10-dependent antigen-specific unresponsiveness. Journal of Immunology 2009, 183(12): 8232-8243.

64.Keir ME, Sharpe AH. The B7/CD28 costimulatory family in autoimmunity. Immunological Reviews 2005, 204: 128-143.

65.Paust S, Lu L, McCarty N, Cantor H. Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proceedings of the National Academy of Sciences of the United States of America 2004, 101(28): 10398-10403.

66.Wohler J, Bullard D, Schoeb T, Barnum S. LFA-1 is critical for regulatory T cell homeostasis and function. Molecular Immunology 2009, 46(11-12): 2424-2428.

67.Coquet JM, Ribot JC, Babala N, Middendorp S, van der Horst G, Xiao Y, et al. Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway. The Journal of Experimental Medicine 2013, 210(4): 715-728.

68.Vu MD, Xiao X, Gao W, Degauque N, Chen M, Kroemer A, et al. OX40 costimulation turns off Foxp3+ Tregs. Blood 2007, 110(7): 2501-2510.

69.Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 2000, 12(4): 431-440.

70.Tai X, Cowan M, Feigenbaum L, Singer A. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nature Immunology 2005, 6(2): 152-162.

71.Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annual Review of Immunology 2004, 22: 531-562.

72.Borst J, Hendriks J, Xiao Y. CD27 and CD70 in T cell and B cell activation. Current Opinion in Immunology 2005, 17(3): 275-281.

73.Peperzak V, Xiao Y, Veraar EA, Borst J. CD27 sustains survival of CTLs in virus-infected nonlymphoid tissue in mice by inducing autocrine IL-2 production. The Journal of Clinical Investigation 2010, 120(1): 168-178.

74.Matter M, Mumprecht S, Pinschewer DD, Pavelic V, Yagita H, Krautwald S, et al. Virus-induced polyclonal B cell activation improves protective CTL memory via retained CD27 expression on memory CTL. European Journal of Immunology 2005, 35(11): 3229-3239.

75.Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nature Reviews Immunology 2003, 3(8): 609-620.

76.Xiao X, Kroemer A, Gao W, Ishii N, Demirci G, Li XC. OX40/OX40L costimulation affects induction of Foxp3+ regulatory T cells in part by expanding memory T cells in vivo. Journal of Immunology 2008, 181(5): 3193-3201.

77.Zheng J, Chan PL, Liu Y, Qin G, Xiang Z, Lam KT, et al. ICOS regulates the generation and function of human CD4+ Treg in a CTLA-4 dependent manner. PloS One 2013, 8(12): e82203.

78.Burmeister Y, Lischke T, Dahler AC, Mages HW, Lam KP, Coyle AJ, et al. ICOS controls the pool size of effector-memory and regulatory T cells. Journal of Immunology 2008, 180(2): 774-782.

79.Chu KH, Chiang BL. Regulatory T cells induced by mucosal B cells alleviate allergic airway hypersensitivity. American Journal of Respiratory Cell and Molecular Biology 2012, 46(5): 651-659.

80.Chen X, Jensen PE. Cutting edge: primary B lymphocytes preferentially expand allogeneic FoxP3+ CD4 T cells. Journal of Immunology 2007, 179(4): 2046-2050.

81.Chen LC, Delgado JC, Jensen PE, Chen X. Direct expansion of human allospecific FoxP3+CD4+ regulatory T cells with allogeneic B cells for therapeutic application. Journal of Immunology 2009, 183(6): 4094-4102.

82.Tu W, Lau YL, Zheng J, Liu Y, Chan PL, Mao H, et al. Efficient generation of human alloantigen-specific CD4+ regulatory T cells from naive precursors by CD40-activated B cells. Blood 2008, 112(6): 2554-2562.

83.Chu KH, Chiang BL. Characterization and functional studies of forkhead box protein 3(-) lymphocyte activation gene 3(+) CD4(+) regulatory T cells induced by mucosal B cells. Clinical and Experimental Immunology 2015, 180(2): 316-328.

84.Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nature Reviews Immunology 2008, 8(7): 523-532.

85.Lassila O, Vainio O, Matzinger P. Can B cells turn on virgin T cells? Nature 1988, 334(6179): 253-255.

86.Fuchs EJ, Matzinger P. B cells turn off virgin but not memory T cells. Science 1992, 258(5085): 1156-1159.

87.Raimondi G, Zanoni I, Citterio S, Ricciardi-Castagnoli P, Granucci F. Induction of peripheral T cell tolerance by antigen-presenting B cells. II. Chronic antigen presentation overrules antigen-presenting B cell activation. Journal of Immunology 2006, 176(7): 4021-4028.

88.Reis e Sousa C. Dendritic cells in a mature age. Nature Reviews Immunology 2006, 6(6): 476-483.

89.Morris SC, Lees A, Finkelman FD. In vivo activation of naive T cells by antigen-presenting B cells. Journal of Immunology 1994, 152(8): 3777-3785.

90.Tsitoura DC, Yeung VP, DeKruyff RH, Umetsu DT. Critical role of B cells in the development of T cell tolerance to aeroallergens. International Immunology 2002, 14(6): 659-667.

91.Earle KE, Tang Q, Zhou X, Liu W, Zhu S, Bonyhadi ML, et al. In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation. Clinical Immunology 2005, 115(1): 3-9.

92.Okamura T, Fujio K, Shibuya M, Sumitomo S, Shoda H, Sakaguchi S, et al. CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2. Proceedings of the National Academy of Sciences of the United States of America 2009, 106(33): 13974-13979.

93.Strauss L, Bergmann C, Szczepanski MJ, Lang S, Kirkwood JM, Whiteside TL. Expression of ICOS on human melanoma-infiltrating CD4+CD25highFoxp3+ T regulatory cells: implications and impact on tumor-mediated immune suppression. Journal of Immunology 2008, 180(5): 2967-2980.

94.Cosmi L, Liotta F, Lazzeri E, Francalanci M, Angeli R, Mazzinghi B, et al. Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. Blood 2003, 102(12): 4107-4114.

95.Ono M, Shimizu J, Miyachi Y, Sakaguchi S. Control of autoimmune myocarditis and multiorgan inflammation by glucocorticoid-induced TNF receptor family-related protein(high), Foxp3-expressing CD25+ and CD25- regulatory T cells. Journal of Immunology 2006, 176(8): 4748-4756.

96.Mills KH. Regulatory T cells: friend or foe in immunity to infection? Nature Reviews Immunology 2004, 4(11): 841-855.

97.Hsu LH, Li KP, Chu KH, Chiang BL. A B-1a cell subset induces Foxp3(-) T cells with regulatory activity through an IL-10-independent pathway. Cellular & Molecular Immunology 2015, 12(3): 354-365.

98.Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, et al. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nature Medicine 2002, 8(9): 1024-1032.

99.Watanabe M, Takagi Y, Kotani M, Hara Y, Inamine A, Hayashi K, et al. Down-regulation of ICOS ligand by interaction with ICOS functions as a regulatory mechanism for immune responses. Journal of Immunology 2008, 180(8): 5222-5234.

100.Wulfing C, Sjaastad MD, Davis MM. Visualizing the dynamics of T cell activation: intracellular adhesion molecule 1 migrates rapidly to the T cell/B cell interface and acts to sustain calcium levels. Proceedings of the National Academy of Sciences of the United States of America 1998, 95(11): 6302-6307.

101.Nakayama T, Yamashita M. The TCR-mediated signaling pathways that control the direction of helper T cell differentiation. Seminars in Immunology 2010, 22(5): 303-309.

102.Powell JD, Ragheb JA, Kitagawa-Sakakida S, Schwartz RH. Molecular regulation of interleukin-2 expression by CD28 co-stimulation and anergy. Immunological Reviews 1998, 165: 287-300.

103.Shahinian A, Pfeffer K, Lee KP, Kundig TM, Kishihara K, Wakeham A, et al. Differential T cell costimulatory requirements in CD28-deficient mice. Science 1993, 261(5121): 609-612.

104.Ross JA, Nagy ZS, Cheng H, Stepkowski SM, Kirken RA. Regulation of T cell homeostasis by JAKs and STATs. Archivum Immunologiae et Therapiae Experimentalis 2007, 55(4): 231-245.

105.Powell JD, Delgoffe GM. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 2010, 33(3): 301-311.

106.Luckheeram RV, Zhou R, Verma AD, Xia B. CD4(+)T cells: differentiation and functions. Clinical & Developmental Immunology 2012, 2012: 925135.

107.Adamson AS, Collins K, Laurence A, O''Shea JJ. The Current STATus of lymphocyte signaling: new roles for old players. Current Opinion in Immunology 2009, 21(2): 161-166.

108.Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nature Reviews Immunology 2003, 3(11): 900-911.

109.Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood 2008, 112(5): 1557-1569.

110.Darnell JE, Jr. STATs and gene regulation. Science 1997, 277(5332): 1630-1635.

111.Levy DE, Darnell JE, Jr. Stats: transcriptional control and biological impact. Nature Reviews Molecular Cell Biology 2002, 3(9): 651-662.

112.Schindler C, Levy DE, Decker T. JAK-STAT signaling: from interferons to cytokines. The Journal of Biological Chemistry 2007, 282(28): 20059-20063.

113.Shuai K, Schindler C, Prezioso VR, Darnell JE, Jr. Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein. Science 1992, 258(5089): 1808-1812.

114.Schindler C, Shuai K, Prezioso VR, Darnell JE, Jr. Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science 1992, 257(5071): 809-813.

115.Zhong Z, Wen Z, Darnell JE, Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 1994, 264(5155): 95-98.

116.Harris TJ, Grosso JF, Yen HR, Xin H, Kortylewski M, Albesiano E, et al. Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. Journal of Immunology 2007, 179(7): 4313-4317.

117.Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell JE, Jr., et al. Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. The Journal of Experimental Medicine 1995, 181(5): 1755-1762.

118.Beadling C, Guschin D, Witthuhn BA, Ziemiecki A, Ihle JN, Kerr IM, et al. Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. The EMBO Journal 1994, 13(23): 5605-5615.

119.Burchill MA, Yang J, Vang KB, Farrar MA. Interleukin-2 receptor signaling in regulatory T cell development and homeostasis. Immunology Letters 2007, 114(1): 1-8.

120.Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL. An interleukin-4-induced transcription factor: IL-4 Stat. Science 1994, 265(5179): 1701-1706.

121.Zhou L, Ivanov, II, Spolski R, Min R, Shenderov K, Egawa T, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunology 2007, 8(9): 967-974.

122.Kaplan MH, Sun YL, Hoey T, Grusby MJ. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 1996, 382(6587): 174-177.

123.Takaki H, Ichiyama K, Koga K, Chinen T, Takaesu G, Sugiyama Y, et al. STAT6 Inhibits TGF-beta1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. The Journal of Biological Chemistry 2008, 283(22): 14955-14962.

124.Wang H, Meng R, Li Z, Yang B, Liu Y, Huang F, et al. IL-27 induces the differentiation of Tr1-like cells from human naive CD4+ T cells via the phosphorylation of STAT1 and STAT3. Immunology Letters 2011, 136(1): 21-28.

125.Delgoffe GM, Vignali DA. STAT heterodimers in immunity: A mixed message or a unique signal? Jak-Stat 2013, 2(1): e23060.

126.Wehinger J, Gouilleux F, Groner B, Finke J, Mertelsmann R, Weber-Nordt RM. IL-10 induces DNA binding activity of three STAT proteins (Stat1, Stat3, and Stat5) and their distinct combinatorial assembly in the promoters of selected genes. FEBS Letters 1996, 394(3): 365-370.

127.Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nature Immunology 2002, 3(6): 549-557.

128.Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007, 448(7152): 484-487.

129.Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006, 24(2): 179-189.

130.Adalid-Peralta L, Fragoso G, Fleury A, Sciutto E. Mechanisms underlying the induction of regulatory T cells and its relevance in the adaptive immune response in parasitic infections. International Journal of Biological Sciences 2011, 7(9): 1412-1426.

131.Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 1996, 4(3): 313-319.

132.Lischke A, Moriggl R, Brandlein S, Berchtold S, Kammer W, Sebald W, et al. The interleukin-4 receptor activates STAT5 by a mechanism that relies upon common gamma-chain. The Journal of Biological Chemistry 1998, 273(47): 31222-31229.

133.Yamashita M, Katsumata M, Iwashima M, Kimura M, Shimizu C, Kamata T, et al. T cell receptor-induced calcineurin activation regulates T helper type 2 cell development by modifying the interleukin 4 receptor signaling complex. The Journal of Experimental Medicine 2000, 191(11): 1869-1879.

134.Yu CR, Mahdi RM, Ebong S, Vistica BP, Chen J, Guo Y, et al. Cell proliferation and STAT6 pathways are negatively regulated in T cells by STAT1 and suppressors of cytokine signaling. Journal of Immunology 2004, 173(2): 737-746.

135.Perez GM, Melo M, Keegan AD, Zamorano J. Aspirin and salicylates inhibit the IL-4- and IL-13-induced activation of STAT6. Journal of Immunology 2002, 168(3): 1428-1434.

136.Simms PE, Ellis TM. Utility of flow cytometric detection of CD69 expression as a rapid method for determining poly- and oligoclonal lymphocyte activation. Clinical and Diagnostic Laboratory Immunology 1996, 3(3): 301-304.

137.Sahoo A, Lee CG, Jash A, Son JS, Kim G, Kwon HK, et al. Stat6 and c-Jun mediate Th2 cell-specific IL-24 gene expression. Journal of Immunology 2011, 186(7): 4098-4109.



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