We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Beyond regulatory T cells: the potential role for IL-2 to deplete T-follicular helper cells and treat autoimmune diseases

    André Ballesteros-Tato

    Department of Medicine, Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, 1825 University Blvd, SHEL 511, Birmingham, AL 35294-2182, USA

    E-mail Address: aballest@uab.edu

    Published Online:https://doi.org/10.2217/imt.14.83

    Low-dose IL-2 administration suppresses unwanted immune responses in mice and humans, thus evidencing the potential of IL-2 to treat autoimmune disorders. Increased Tregs activity is one of the potential mechanisms by which low-dose IL-2 immunotherapy induces immunosuppression. In addition, recent data indicate that IL-2 may contribute to prevent unwanted self-reactive responses by preventing the developing of T-follicular helper cells, a CD4+ T-cell subset that expands in autoimmune disease patients and promotes long-term effector B-cell responses. Here we discuss the mechanisms underlying the clinical benefits of low-dose IL-2 administration, focusing on the role of this cytokine in promoting Treg-mediated suppression and preventing self-reactive T-follicular helper cell responses.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 193(4257), 1007–1008 (1976).
    • 2 Wagner H, Hardt C, Heeg K, Rollinghoff M, Pfizenmaier K. T-cell-derived helper factor allows in vivo induction of cytotoxic T cells in nu/nu mice. Nature 284(5753), 278–278 (1980).
    • 3 Henney CS, Kuribayashi K, Kern DE, Gillis S. Interleukin-2 augments natural killer cell activity. Nature 291(5813), 335–338 (1981).
    • 4 Rosenberg SA. Raising the bar: the curative potential of human cancer immunotherapy. Sci. Transl. Med. 4(127), 127ps128 (2012).
    • 5 Pett SL, Kelleher AD, Emery S. Role of interleukin-2 in patients with HIV infection. Drugs 70(9), 1115–1130 (2010).
    • 6 Schwartzentruber DJ, Lawson DH, Richards JM et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N. Engl. J. Med. 364(22), 2119–2127 (2011).
    • 7 Rosenberg SA, Yannelli JR, Yang JC et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J. Natl Cancer Inst. 86(15), 1159–1166 (1994).
    • 8 Rosenberg SA, Yang JC, Sherry RM et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17(13), 4550–4557 (2011).
    • 9 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(3), 1151–1164 (1995).• First study characterizing Tregs.
    • 10 Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564 (2012).
    • 11 Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature 441(7095), 890–893 (2006).
    • 12 Pipkin ME, Sacks JA, Cruz-Guilloty F, Lichtenheld MG, Bevan MJ, Rao A. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32(1), 79–90 (2010).
    • 13 Kalia V, Sarkar S, Subramaniam S, Haining WN, Smith KA, Ahmed R. Prolonged interleukin-2Ralpha expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity 32(1), 91–103 (2010).
    • 14 Lenardo MJ. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature 353(6347), 858–861 (1991).
    • 15 Liao W, Lin JX, Leonard WJ. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr. Opin. Immunol. 23(5), 598–604 (2011).
    • 16 Laurence A, Tato CM, Davidson TS et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26(3), 371–381 (2007).
    • 17 Ballesteros-Tato A, Leon B, Graf BA et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36(5), 847–856 (2012).• Demonstrates that IL-2 administration prevents the development of T-follicular helper (Tfh) cells following influenza virus infection.
    • 18 Oestreich KJ, Mohn SE, Weinmann AS. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat. Immunol. 13(4), 405–411 (2012).
    • 19 Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S. STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 209(2), 243–250 (2012).
    • 20 Nurieva RI, Podd A, Chen Y et al. STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J. Biol. Chem. 287(14), 11234–11239 (2012).
    • 21 Leon B, Bradley JE, Lund FE, Randall TD, Ballesteros-Tato A. FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat. Commun. 5, 3495 (2014).
    • 22 Crotty S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).
    • 23 Suzuki H, Duncan GS, Takimoto H, Mak TW. Abnormal development of intestinal intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor beta chain. J. Exp. Med. 185(3), 499–505 (1997).
    • 24 Sadlack B, Lohler J, Schorle H et al. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur. J. Immunol. 25(11), 3053–3059 (1995).
    • 25 Suzuki H, Kundig TM, Furlonger C et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 268(5216), 1472–1476 (1995).
    • 26 Sharfe N, Dadi HK, Shahar M, Roifman CM. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc. Natl Acad. Sci. USA 94(7), 3168–3171 (1997).
    • 27 Caudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J. Allergy Clin. Immunol. 119(2), 482–487 (2007).
    • 28 Roifman CM. Human IL-2 receptor alpha chain deficiency. Pediatr. Res. 48(1), 6–11 (2000).
    • 29 Cheng G, Yu A, Dee MJ, Malek TR. IL-2R signaling is essential for functional maturation of regulatory T cells during thymic development. J. Immunol. 190(4), 1567–1575 (2013).
    • 30 Yuan X, Cheng G, Malek TR. The importance of regulatory T-cell heterogeneity in maintaining self-tolerance. Immunol. Rev. 259(1), 103–114 (2014).
    • 31 Saadoun D, Rosenzwajg M, Joly F et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N. Engl. J. Med. 365(22), 2067–2077 (2011).• Low-dose rIL-2 treatment significantly increases Tregs and improves vasculitis in patients with hepatitis C virus-induced vasculitis.
    • 32 Matsuoka K, Koreth J, Kim HT et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci. Transl. Med. 5(179), 179ra143 (2013).
    • 33 Hartemann A, Bensimon G, Payan CA et al. Low-dose interleukin 2 in patients with type 1 diabetes: a Phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 1(4), 295–305 (2013).
    • 34 Kennedy-Nasser AA, Ku S, Castillo-Caro P et al. Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity. Clin. Cancer Res. 20(8), 2215–2225 (2014).
    • 35 Baeyens A, Perol L, Fourcade G et al. Limitations of IL-2 and rapamycin in immunotherapy of type 1 diabetes. Diabetes 62(9), 3120–3131 (2013).
    • 36 Malek TR. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).
    • 37 Zelante T, Fric J, Wong AY, Ricciardi-Castagnoli P. Interleukin-2 production by dendritic cells and its immuno-regulatory functions. Front. Immunol. 3, 161 (2012).
    • 38 Harris DP, Haynes L, Sayles PC et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat. Immunol. 1(6), 475–482 (2000).
    • 39 Wang X, Rickert M, Garcia KC. Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors. Science 310(5751), 1159–1163 (2005).
    • 40 Rickert M, Wang X, Boulanger MJ, Goriatcheva N, Garcia KC. The structure of interleukin-2 complexed with its alpha receptor. Science 308(5727), 1477–1480 (2005).
    • 41 Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38(1), 13–25 (2013).
    • 42 Brennan P, Babbage JW, Burgering BM, Groner B, Reif K, Cantrell DA. Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity 7(5), 679–689 (1997).
    • 43 Walker SR, Nelson EA, Frank DA. STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas. Oncogene 26(2), 224–233 (2007).
    • 44 Fukao T, Koyasu S. Expression of functional IL-2 receptors on mature splenic dendritic cells. Eur. J. Immunol. 30(5), 1453–1457 (2000).
    • 45 Wuest SC, Edwan JH, Martin JF et al. A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nat. Med. 17(5), 604–609 (2011).
    • 46 Sabatos CA, Doh J, Chakravarti S et al. A synaptic basis for paracrine interleukin-2 signaling during homotypic T cell interaction. Immunity 29(2), 238–248 (2008).
    • 47 Huse M, Lillemeier BF, Kuhns MS, Chen DS, Davis MM. T cells use two directionally distinct pathways for cytokine secretion. Nat. Immunol. 7(3), 247–255 (2006).
    • 48 Granucci F, Feau S, Angeli V, Trottein F, Ricciardi-Castagnoli P. Early IL-2 production by mouse dendritic cells is the result of microbial-induced priming. J. Immunol. 170(10), 5075–5081 (2003).
    • 49 Kulhankova K, Rouse T, Nasr ME, Field EH. Dendritic cells control CD4+CD25+ Treg cell suppressor function in vitro through juxtacrine delivery of IL-2. PLoS ONE 7(9), e43609 (2012).
    • 50 Tokano Y, Murashima A, Takasaki Y, Hashimoto H, Okumura K, Hirose S. Relation between soluble interleukin 2 receptor and clinical findings in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 48(10), 803–809 (1989).
    • 51 Sawada S, Hashimoto H, Iijma S et al. Increased soluble IL-2 receptor in serum of patients with systemic lupus erythematosus. Clin. Rheumatol. 12(2), 204–209 (1993).
    • 52 Ward MM, Dooley MA, Christenson VD, Pisetsky DS. The relationship between soluble interleukin 2 receptor levels and antidouble stranded DNA antibody levels in patients with systemic lupus erythematosus. J. Rheumatol. 18(2), 235–240 (1991).
    • 53 Ter Borg EJ, Horst G, Limburg PC, Kallenberg CG. Changes in plasma levels of interleukin-2 receptor in relation to disease exacerbations and levels of anti-dsDNA and complement in systemic lupus erythematosus. Clin. Exp. Immunol. 82(1), 21–26 (1990).
    • 54 Maier LM, Lowe CE, Cooper J et al. IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production. PLoS Genet. 5(1), e1000322 (2009).
    • 55 Maier LM, Anderson DE, Severson CA et al. Soluble IL-2RA levels in multiple sclerosis subjects and the effect of soluble IL-2RA on immune responses. J. Immunol. 182(3), 1541–1547 (2009).
    • 56 Russell SE, Moore AC, Fallon PG, Walsh PT. Soluble IL-2Ralpha (sCD25) exacerbates autoimmunity and enhances the development of Th17 responses in mice. PLoS ONE 7(10), e47748 (2012).
    • 57 Bilate AM, Lafaille JJ. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu. Rev. Immunol. 30, 733–758 (2012).
    • 58 Abbas AK, Benoist C, Bluestone JA et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat. Immunol. 14(4), 307–308 (2013).
    • 59 Bennett CL, Christie J, Ramsdell F et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27(1), 20–21 (2001).
    • 60 Wildin RS, Ramsdell F, Peake J et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27(1), 18–20 (2001).
    • 61 Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8(2), 191–197 (2007).
    • 62 Brunkow ME, Jeffery EW, Hjerrild KA et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27(1), 68–73 (2001).
    • 63 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 17(2), 167–178 (2002).
    • 64 Lio CW, Hsieh CS. A two-step process for thymic regulatory T cell development. Immunity 28(1), 100–111 (2008).
    • 65 Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6(11), 1142–1151 (2005).
    • 66 D'Cruz LM, Klein L. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat. Immunol. 6(11), 1152–1159 (2005).
    • 67 Bayer AL, Yu A, Malek TR. Function of the IL-2R for thymic and peripheral CD4+CD25+ Foxp3+ T regulatory cells. J. Immunol. 178(7), 4062–4071 (2007).
    • 68 Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA. IL-2 is essential for TGF-beta to convert naive CD4+CD25- cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J. Immunol. 178(4), 2018–2027 (2007).
    • 69 Davidson TS, Dipaolo RJ, Andersson J, Shevach EM. Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J. Immunol. 178(7), 4022–4026 (2007).
    • 70 Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol. 178(1), 280–290 (2007).
    • 71 Yao Z, Kanno Y, Kerenyi M et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109(10), 4368–4375 (2007).
    • 72 Vang KB, Yang J, Mahmud SA, Burchill MA, Vegoe AL, Farrar MA. IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development. J. Immunol. 181(5), 3285–3290 (2008).
    • 73 Bayer AL, Lee JY, De La Barrera A, Surh CD, Malek TR. A function for IL-7R for CD4+CD25+Foxp3+ T regulatory cells. J. Immunol. 181(1), 225–234 (2008).
    • 74 Furtado GC, Curotto De Lafaille MA, Kutchukhidze N, Lafaille JJ. Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J. Exp. Med. 196(6), 851–857 (2002).
    • 75 Yamanouchi J, Rainbow D, Serra P et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat. Genet. 39(3), 329–337 (2007).
    • 76 Brand OJ, Lowe CE, Heward JM et al. Association of the interleukin-2 receptor alpha (IL-2Ralpha)/CD25 gene region with Graves' disease using a multilocus test and tag SNPs. Clin. Endocrinol. 66(4), 508–512 (2007).
    • 77 Matesanz F, Fedetz M, Collado-Romero M et al. Allelic expression and interleukin-2 polymorphisms in multiple sclerosis. J. NeuroImmunol. 119(1), 101–105 (2001).
    • 78 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447(7145), 661–678 (2007).
    • 79 Vella A, Cooper JD, Lowe CE et al. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76(5), 773–779 (2005).
    • 80 Lowe CE, Cooper JD, Brusko T et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat. Genet. 39(9), 1074–1082 (2007).
    • 81 Hafler DA, Compston A, Sawcer S et al. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357(9), 851–862 (2007).
    • 82 Lieberman LA, Tsokos GC. The IL-2 defect in systemic lupus erythematosus disease has an expansive effect on host immunity. J. BioMed. Biotechnol. 2010, 740619 (2010).
    • 83 Hulme MA, Wasserfall CH, Atkinson MA, Brusko TM. Central role for interleukin-2 in type 1 diabetes. Diabetes 61(1), 14–22 (2012).
    • 84 Kitas GD, Salmon M, Farr M, Gaston JS, Bacon PA. Deficient interleukin 2 production in rheumatoid arthritis: association with active disease and systemic complications. Clin. Exp. Immunol. 73(2), 242–249 (1988).
    • 85 Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat. Rev. Immunol. 7(8), 585–598 (2007).
    • 86 Grinberg-Bleyer Y, Baeyens A, You S et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J. Exp. Med. 207(9), 1871–1878 (2010).
    • 87 Koreth J, Matsuoka K, Kim HT et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N. Engl. J. Med. 365(22), 2055–2066 (2011).•• Demonstrates that patients with chronic graft-versus-host disease respond to low-dose IL-2 treatment.
    • 88 Churlaud G, Jimenez V, Ruberte J et al. Sustained stimulation and expansion of Tregs by IL2 control autoimmunity without impairing immune responses to infection, vaccination and cancer. Clin. Immunol. 151(2), 114–126 (2014).
    • 89 Humrich JY, Morbach H, Undeutsch R et al. Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus. Proc. Natl Acad. Sci. USA 107(1), 204–209 (2010).• Indicates that IL-2 shortage and autoimmune disease progression in lupus prone mice can be prevented by exogenous IL-2 administration.
    • 90 Tang Q, Henriksen KJ, Bi M et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J. Exp. Med. 199(11), 1455–1465 (2004).
    • 91 Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J. Exp. Med. 199(11), 1467–1477 (2004).
    • 92 Diaz-De-Durana Y, Lau J, Knee D et al. IL-2 immunotherapy reveals potential for innate beta cell regeneration in the non-obese diabetic mouse model of autoimmune diabetes. PLoS ONE 8(10), e78483 (2013).
    • 93 Tang Q, Adams JY, Penaranda C et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28(5), 687–697 (2008).• Demonstrates that administration of low doses of rIL2 prevented the onset of diabetes in young prediabetic-female non-obese diabetic mice.
    • 94 Dendrou CA, Plagnol V, Fung E et al. Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nat. Genet. 41(9), 1011–1015 (2009).
    • 95 Garg G, Tyler JR, Yang JH et al. Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function. J. Immunol. 188(9), 4644–4653 (2012).
    • 96 Wofsy D, Dauphinee MJ, Kipper SB, Talal N. Interleukin-2 deficiency in murine systemic lupus erythematosus. Transact. Assoc. Am. Phys. 94, 341–348 (1981).
    • 97 Solomou EE, Juang YT, Gourley MF, Kammer GM, Tsokos GC. Molecular basis of deficient IL-2 production in T cells from patients with systemic lupus erythematosus. J. Immunol. 166(6), 4216–4222 (2001).
    • 98 Linker-Israeli M, Bakke AC, Kitridou RC, Gendler S, Gillis S, Horwitz DA. Defective production of interleukin 1 and interleukin 2 in patients with systemic lupus erythematosus (SLE). J. Immunol. 130(6), 2651–2655 (1983).
    • 99 Rabinovitch A, Suarez-Pinzon WL, Shapiro AM, Rajotte RV, Power R. Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice. Diabetes 51(3), 638–645 (2002).
    • 100 Yu A, Zhu L, Altman NH, Malek TR. A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity 30(2), 204–217 (2009).
    • 101 Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat. Immunol. 8(12), 1353–1362 (2007).
    • 102 Ito S, Bollard CM, Carlsten M et al. Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory T cells and natural killer cells in healthy volunteers. Mol. Ther. 22(7), 1388–1395 (2014).
    • 103 Krieg C, Letourneau S, Pantaleo G, Boyman O. Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells. Proc. Natl Acad. Sci. USA 107(26), 11906–11911 (2010).• Demonstrates that antibody JES6-1, as the IL-2/JES6-1 complex, selectively targets CD25-expressing cells and expands Tregs more efficiently than IL-2 administration alone.
    • 104 Lee SY, Cho ML, Oh HJ et al. Interleukin-2/anti-interleukin-2 monoclonal antibody immune complex suppresses collagen-induced arthritis in mice by fortifying interleukin-2/STAT5 signalling pathways. Immunol. 137(4), 305–316 (2012).
    • 105 Webster KE, Walters S, Kohler RE et al. In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J. Exp. Med. 206(4), 751–760 (2009).
    • 106 Liu R, Zhou Q, La Cava A, Campagnolo DI, Van Kaer L, Shi FD. Expansion of regulatory T cells via IL-2/anti-IL-2 mAb complexes suppresses experimental myasthenia. Eur. J. Immunol. 40(6), 1577–1589 (2010).
    • 107 Shapiro AM, Suarez-Pinzon WL, Power R, Rabinovitch A. Combination therapy with low dose sirolimus and tacrolimus is synergistic in preventing spontaneous and recurrent autoimmune diabetes in non-obese diabetic mice. Diabetologia 45(2), 224–230 (2002).
    • 108 Walsh PT, Buckler JL, Zhang J et al. PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs. J. Clin. Invest. 116(9), 2521–2531 (2006).
    • 109 Long SA, Rieck M, Sanda S et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes 61(9), 2340–2348 (2012).
    • 110 Ballesteros-Tato A, Randall TD. Priming of T follicular helper cells by dendritic cells. Immunol. Cell Biol. 92(1), 22–27 (2014).
    • 111 Yu D, Rao S, Tsai LM et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31(3), 457–468 (2009).
    • 112 Nurieva RI, Chung Y, Martinez GJ et al. Bcl6 mediates the development of T follicular helper cells. Science 325(5943), 1001–1005 (2009).
    • 113 Johnston RJ, Poholek AC, Ditoro D et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325(5943), 1006–1010 (2009).
    • 114 Goodnow CC, Vinuesa CG, Randall KL, Mackay F, Brink R. Control systems and decision making for antibody production. Nat. Immunol. 11(8), 681–688 (2010).
    • 115 Han S, Hathcock K, Zheng B, Kepler TB, Hodes R, Kelsoe G. Cellular interaction in germinal centers. Roles of CD40 ligand and B7–2 in established germinal centers. J. Immunol. 155(2), 556–567 (1995).
    • 116 Linterman MA, Beaton L, Yu D et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 207(2), 353–363 (2010).
    • 117 Vogelzang A, Mcguire HM, Yu D, Sprent J, Mackay CR, King C. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29(1), 127–137 (2008).
    • 118 Bryant VL, Ma CS, Avery DT et al. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5+ T follicular helper cells. J. Immunol. 179(12), 8180–8190 (2007).
    • 119 Allen CD, Okada T, Cyster JG. Germinal-center organization and cellular dynamics. Immunity 27(2), 190–202 (2007).
    • 120 Chang A, Henderson SG, Brandt D et al. In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J. Immunol. 186(3), 1849–1860 (2011).
    • 121 Pugh-Bernard AE, Silverman GJ, Cappione AJ et al. Regulation of inherently autoreactive VH4–34 B cells in the maintenance of human B cell tolerance. J. Clin. Invest. 108(7), 1061–1070 (2001).
    • 122 Arce E, Jackson DG, Gill MA, Bennett LB, Banchereau J, Pascual V. Increased frequency of pre-germinal center B cells and plasma cell precursors in the blood of children with systemic lupus erythematosus. J. Immunol. 167(4), 2361–2369 (2001).
    • 123 Grammer AC, Slota R, Fischer R et al. Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. J. Clin. Invest. 112(10), 1506–1520 (2003).
    • 124 Weyand CM, Goronzy JJ. Ectopic germinal center formation in rheumatoid synovitis. Ann. NY Acad. Sci. 987, 140–149 (2003).
    • 125 Ding Y, Li J, Wu Q et al. IL-17RA is essential for optimal localization of follicular Th cells in the germinal center light zone to promote autoantibody-producing B cells. J. Immunol. 191(4), 1614–1624 (2013).
    • 126 Luzina IG, Atamas SP, Storrer CE et al. Spontaneous formation of germinal centers in autoimmune mice. J. leukocyte Biol. 70(4), 578–584 (2001).
    • 127 Wang JH, New JS, Xie S et al. Extension of the germinal center stage of B cell development promotes autoantibodies in BXD2 mice. Arthritis Rheum. 65(10), 2703–2712 (2013).
    • 128 Kendall PL, Yu G, Woodward EJ, Thomas JW. Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes. J. Immunol. 178(9), 5643–5651 (2007).
    • 129 Schroder AE, Greiner A, Seyfert C, Berek C. Differentiation of B cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis. Proc. Natl Acad. Sci. USA 93(1), 221–225 (1996).
    • 130 Baumjohann D, Preite S, Reboldi A et al. Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype. Immunity 38(3), 596–605 (2013).
    • 131 Deenick EK, Chan A, Ma CS et al. Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling. Immunity 33(2), 241–253 (2010).
    • 132 Leon B, Ballesteros-Tato A, Browning JL, Dunn R, Randall TD, Lund FE. Regulation of T(H)2 development by CXCR5+ dendritic cells and lymphotoxin-expressing B cells. Nat. Immunol. 13(7), 681–690 (2012).
    • 133 Angeli V, Ginhoux F, Llodra J et al. B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24(2), 203–215 (2006).
    • 134 Leon B, Ballesteros-Tato A, Misra RS, Wojciechowski W, Lund FE. Unraveling effector functions of B cells during infection: the hidden world beyond antibody production. Infect. Disord. Drug Targets 12(3), 213–221 (2012).
    • 135 Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N. Engl. J. Med. 361(22), 2143–2152 (2009).
    • 136 Merrill JT, Neuwelt CM, Wallace DJ et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, Phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 62(1), 222–233 (2010).
    • 137 Merrill J, Buyon J, Furie R et al. Assessment of flares in lupus patients enrolled in a Phase II/III study of rituximab (EXPLORER). Lupus 20(7), 709–716 (2011).
    • 138 Rovin BH, Furie R, Latinis K et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 64(4), 1215–1226 (2012).
    • 139 Sanz I, Lee FE. B cells as therapeutic targets in SLE. Nat. Rev. Rheumatol. 6(6), 326–337 (2010).
    • 140 Dilillo DJ, Hamaguchi Y, Ueda Y et al. Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. J. Immunol. 180(1), 361–371 (2008).
    • 141 Ahuja A, Anderson SM, Khalil A, Shlomchik MJ. Maintenance of the plasma cell pool is independent of memory B cells. Proc. Natl Acad. Sci. USA 105(12), 4802–4807 (2008).
    • 142 Bekar KW, Owen T, Dunn R et al. Prolonged effects of short-term anti-CD20 B cell depletion therapy in murine systemic lupus erythematosus. Arthritis Rheum. 62(8), 2443–2457 (2010).
    • 143 Ma CS, Deenick EK. Human T follicular helper (Tfh) cells and disease. Immunol. Cell Biol. 92(1), 64–71 (2013).
    • 144 Tangye SG, Ma CS, Brink R, Deenick EK. The good, the bad and the ugly - TFH cells in human health and disease. Nat. Rev. Immunol. 13(6), 412–426 (2013).
    • 145 Simpson N, Gatenby PA, Wilson A et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum. 62(1), 234–244 (2010).
    • 146 Luo C, Li Y, Liu W et al. Expansion of circulating counterparts of follicular helper T cells in patients with myasthenia gravis. J. NeuroImmunol. 256(1–2), 55–61 (2013).
    • 147 Zhu C, Ma J, Liu Y et al. Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J. Clin. Endocrinol. Metabol. 97(3), 943–950 (2012).
    • 148 Liu R, Wu Q, Su D et al. A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis Res. Ther. 14(6), R255 (2012).
    • 149 Ma J, Zhu C, Ma B et al. Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis. Clin. Dev. Immunol. 2012, 827480 (2012).
    • 150 Wang J, Shan Y, Jiang Z et al. High frequencies of activated B cells and T follicular helper cells are correlated with disease activity in patients with new-onset rheumatoid arthritis. Clin. Exp. Immunol. 174(2), 212–220 (2013).
    • 151 Xu X, Shi Y, Cai Y et al. Inhibition of increased circulating Tfh cell by anti-CD20 monoclonal antibody in patients with type 1 diabetes. PLoS ONE 8(11), e79858 (2013).
    • 152 He J, Tsai LM, Leong YA et al. Circulating precursor CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity 39(4), 770–781 (2013).
    • 153 Rankin AL, Guay H, Herber D et al. IL-21 receptor is required for the systemic accumulation of activated B and T lymphocytes in MRL/MpJ-Fas(lpr/lpr)/J mice. J. Immunol. 188(4), 1656–1667 (2012).
    • 154 Bubier JA, Sproule TJ, Foreman O et al. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc. Natl Acad. Sci. USA 106(5), 1518–1523 (2009).
    • 155 Herber D, Brown TP, Liang S, Young DA, Collins M, Dunussi-Joannopoulos K. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R. Fc reduces disease progression. J. Immunol. 178(6), 3822–3830 (2007).
    • 156 Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299(5609), 1033–1036 (2003).
    • 157 Choi YS, Eto D, Yang JA, Lao C, Crotty S. Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation. J. Immunol. 190(7), 3049–3053 (2013).
    • 158 Harker JA, Lewis GM, Mack L, Zuniga EI. Late interleukin-6 escalates T follicular helper cell responses and controls a chronic viral infection. Science 334(6057), 825–829 (2011).
    • 159 Nakayamada S, Poholek AC, Lu KT et al. Type I IFN induces binding of STAT1 to Bcl6: divergent roles of STAT family transcription factors in the T follicular helper cell genetic program. J. Immunol. 192(5), 2156–2166 (2014).
    • 160 Nurieva RI, Chung Y, Hwang D et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29(1), 138–149 (2008).