Abstract
Thymic-derived, regulatory T cells (Treg) represent a subset of CD4+ T cells that are required for normal immune homeostasis and suppression of unwanted responses against self-antigens (Ags) that prevent autoimmunity. Their role as immune regulators and potent ability to suppress T cell responses has been the focus of intense investigations aimed at utilizing these cells therapeutically, particularly in the settings of autoimmunity and transplantation. Many methods for expanding Treg have been described; however, efforts to generate large numbers of Treg for use in vivo often compromise their suppressor function or rely on the induction of Treg rather than their expansion. Our recent studies have focused on the barrier tissue-derived cytokine IL-33, a recently described IL-1 family member. IL-33 has emerged as a multifunctional protein, with reported roles in driving potent Type 1 and Type 2 immunity, as well as facilitating profound Treg expansion in vitro and in vivo. IL-33-expanded Treg express the IL-33 receptor (R) ST2, and express classical markers associated with Treg phenotype and suppressor function. They suppress both CD4+ and CD8+ T cell proliferation and effector functions in vitro, and Treg expressing ST2 have been identified as important regulators of detrimental immune responses in vivo. In the present chapter, we detail methods for expanding significant numbers of Treg using IL-33 both in vitro and in vivo that may potentially be used to promote/maintain organ transplant tolerance or suppress autoimmunity.
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References
Bennett CL, Christie J, Ramsdell F et al (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27(1):20–21
Wildin RS, Ramsdell F, Peake J et al (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27(1):18–20
Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4 + CD25+ regulatory T cells. Nat Immunol 4(4):330–336
McMurchy AN, Bushell A, Levings MK, Wood KJ (2011) Moving to tolerance: clinical application of T regulatory cells. Semin Immunol 23(4):304–313
Tang Q, Bluestone JA, Kang SM (2012) CD4(+)Foxp3(+) regulatory T cell therapy in transplantation. J Mol Cell Biol 4(1):11–21
Verbsky JW (2007) Therapeutic use of T regulatory cells. Curr Opin Rheumatol 19(3):252–258
Shevach EM (2011) Biological functions of regulatory T cells. Adv Immunol 112:137–176
Campbell DJ, Koch MA (2011) Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol 11(2):119–130
Almeida AR, Legrand N, Papiernik M, Freitas AA (2002) Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J Immunol 169(9):4850–4860
Hoffmann P, Eder R, Kunz-Schughart LA et al (2004) Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells. Blood 104(3):895–903
Matta BM, Lott JM, Mathews LR et al (2014) IL-33 is an unconventional alarmin that stimulates IL-2 secretion by dendritic cells to selectively expand IL-33R/ST2+ regulatory T cells. J Immunol 193(8):4010–4020
Turnquist HR, Zhao Z, Rosborough BR et al (2011) IL-33 expands suppressive CD11b + Gr-1(int) and regulatory T cells, including ST2L+ Foxp3+ cells, and mediates regulatory T cell-dependent promotion of cardiac allograft survival. J Immunol 187(9):4598–4610
Brunner SM, Schiechl G, Falk W et al (2011) Interleukin-33 prolongs allograft survival during chronic cardiac rejection. Transpl Int 24(10):1027–1039
Schiering C, Krausgruber T, Chomka A et al (2014) The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513(7519):564–568
Liew FY, Pitman NI, McInnes IB (2010) Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol 10(2):103–110
Schmitz J, Owyang A, Oldham E et al (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23(5):479–490
Liu Q, Turnquist HR (2013) Implications for interleukin-33 in solid organ transplantation. Cytokine 62(2):183–194
Humphreys NE, Xu D, Hepworth MR et al (2008) IL-33, a potent inducer of adaptive immunity to intestinal nematodes. J Immunol 180(4):2443–2449
Yang Q, Li G, Zhu Y et al (2011) IL-33 synergizes with TCR and IL-12 signaling to promote the effector function of CD8+ T cells. Eur J Immunol 41(11):3351–3360
Bourgeois E, Van LP, Samson M et al (2009) The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma production. Eur J Immunol 39(4):1046–1055
Bonilla WV, Frohlich A, Senn K et al (2012) The alarmin interleukin-33 drives protective antiviral CD8(+) T cell responses. Science 335(6071):984–989
Acknowledgements
Many of these protocols were developed in studies with the support National Institutes of Health (NIH) grants to B.M.M. (T32 AI074490) and H.R.T. (R00 HL097155). H.R.T. was also supported by the American Society of Transplantation (AST) Basic Science Faculty Grant, Roche Organ Transplantation Foundation Grant (ROTRF; 58911427) and the American Heart Association Grant-in-Aid (AHA; 14GRNT20400004).
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Matta, B.M., Turnquist, H.R. (2016). Expansion of Regulatory T Cells In Vitro and In Vivo by IL-33. In: Cuturi, M., Anegon, I. (eds) Suppression and Regulation of Immune Responses. Methods in Molecular Biology, vol 1371. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3139-2_3
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DOI: https://doi.org/10.1007/978-1-4939-3139-2_3
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-3138-5
Online ISBN: 978-1-4939-3139-2
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