TSLP directly impairs pulmonary Treg function: association with aberrant tolerogenic immunity in asthmatic airway

Allergy, Asthma & Clinical Immunology - Tập 6 Số 1 - 2010
Khoa D. Nguyen1, Christopher Vanichsarn1, Kari Nadeau1
1Department of Pediatrics, Stanford University, Stanford, CA USA

Tóm tắt

Abstract Background Even though thymic stromal lymphopoietin (TSLP) has been implicated in the development of allergic inflammation, its influence on immune tolerance mediated by regulatory T cells (Treg) have not been explored. We aimed to dissect the influence of TSLP on immunosuppressive activities of Treg and its potential consequences in human allergic asthma. Methods I n vitro culture system was utilized to study the effects of TSLP on human Treg. The functional competency of pulmonary Treg from a cohort of 15 allergic asthmatic, 15 healthy control, and 15 non-allergic asthmatic subjects was also evaluated by suppression assays and flow cytometric analysis. Results Activated pulmonary Treg expressed TSLP-R and responded to TSLP-mediated activation of STAT5. TSLP directly and selectively impaired IL-10 production of Treg and inhibited their suppressive activity. In human allergic asthma, pulmonary Treg exhibited a significant decrease in suppressive activity and IL-10 production compared to healthy control and non-allergic asthmatic counterparts. These functional alterations were associated with elevated TSLP expression in bronchoaveolar lavage fluid (BAL) of allergic asthmatic subjects. Furthermore, allergic asthmatic BAL could suppress IL-10 production by healthy control pulmonary Treg in a TSLP-dependent manner. Conclusions These results provide the first evidences for a direct role of TSLP in the regulation of suppressive activities of Treg. TSLP mediated inhibition of Treg function might present a novel pathologic mechanism to dampen tolerogenic immune responses in inflamed asthmatic airway.

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Tài liệu tham khảo

Vosshenrich CA, Cumano A, Müller W, Di Santo JP, Vieira P: Thymic stromal-derived lymphopoietin distinguishes fetal from adult B cell development. Nat Immunol. 2003, 4: 773-779. 10.1038/ni956.

Al-Shami A: A role for thymic stromal lymphopoietin in CD4(+) T cell development. J Exp Med. 2004, 200: 159-168. 10.1084/jem.20031975.

Soumelis V: Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002, 3: 673-680.

Zhou B: Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol. 2005, 6: 1047-1053. 10.1038/ni1247.

Rochman I, Watanabe N, Arima K, Liu YJ, Leonard WJ: Cutting edge: direct action of thymic stromal lymphopoietin on activated human CD4+ T cells. J Immunol. 2007, 178: 6720-6724.

Akamatsu T: Human TSLP directly enhances expansion of CD8+ T cells. Clin Exp Immunol. 2008, 154: 98-106. 10.1111/j.1365-2249.2008.03731.x.

He R: TSLP acts on infiltrating effector T cells to drive allergic skin inflammation. Proc Natl Acad Sci USA. 2008, 105: 11875-11880. 10.1073/pnas.0801532105.

Al-Shami A, Spolski R, Kelly J, Keane-Myers A, Leonard WJ: A role for TSLP in the development of inflammation in an asthma model. J Exp Med. 2005, 202: 829-839. 10.1084/jem.20050199.

Zhang Z: Thymic stromal lymphopoietin overproduced by keratinocytes in mouse skin aggravates experimental asthma. Proc Natl Acad Sci USA. 2009, 106: 1536-1541. 10.1073/pnas.0812668106.

Akdis CA, Akdis M: Mechanisms and treatment of allergic disease in the big picture of regulatory T cells. J Allergy Clin Immunol. 2009, 123: 735-746. 10.1016/j.jaci.2009.03.034.

Herrick CA, Bottomly K: To respond or not to respond: T cells in allergic asthma. Nat Rev Immunol. 2003, 3: 405-412. 10.1038/nri1084.

Miyara M, Sakaguchi S: Natural regulatory T cells: mechanisms of suppression. Trends Mol Med. 2007, 13: 108-116. 10.1016/j.molmed.2007.01.003.

Hartl D: Quantitative and functional impairment of pulmonary CD4+CD25hi regulatory T cells in pediatric asthma. J Allergy Clin Immunol. 2007, 119: 1258-1266. 10.1016/j.jaci.2007.02.023.

Kearley J, Robinson DS, Lloyd CM: CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling. J Allergy Clin Immunol. 2008, 122: 617-624. 10.1016/j.jaci.2008.05.048.

Presser K: Coexpression of TGF-beta1 and IL-10 enables regulatory T cells to completely suppress airway hyperreactivity. J Immunol. 2008, 181: 7751-7758.

Zuany-Amorim C: Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med. 2002, 8: 625-629. 10.1038/nm0602-625.

Hammad H: Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells. J Exp Med. 2007, 204: 357-367. 10.1084/jem.20061196.

Watanabe N: Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature. 2005, 436: 1181-1185. 10.1038/nature03886.

Jiang Q, Coffield VM, Kondo M, Su L: TSLP is involved in expansion of early thymocyte progenitors. BMC Immunol. 2007, 8: 11-10.1186/1471-2172-8-11.

Mazzucchelli R: Development of regulatory T cells requires IL-7Ralpha stimulation by IL-7 or TSLP. Blood. 2008, 112: 3283-3292. 10.1182/blood-2008-02-137414.

Pandey A: Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin. Nat Immunol. 2000, 1: 59-64. 10.1038/76923.

Park LS: Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: formation of a functional heteromeric complex requires interleukin 7 receptor. J Exp Med. 2000, 192: 659-670. 10.1084/jem.192.5.659.

Quentmeier H: Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation. Leukemia. 2001, 8: 1286-1292. 10.1038/sj.leu.2402175.

Ito T: TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med. 2005, 202: 1213-1223. 10.1084/jem.20051135.

Gilliet M: Human dendritic cells activated by TSLP and CD40L induce proallergic cytotoxic T cells. J Exp Med. 2003, 197: 1059-1063. 10.1084/jem.20030240.

Thornton AM, Shevach EM: CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998, 188: 287-10.1084/jem.188.2.287.

Shevach EM: Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009, 30: 636-645. 10.1016/j.immuni.2009.04.010.

Vignali DA, Collison LW, Workman CJ: How regulatory T cells work. Nat Rev Immunol. 2008, 8: 523-532. 10.1038/nri2343.

Tang Q, Bluestone J: The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol. 2008, 9: 239-244. 10.1038/ni1572.

Wing K, Sakaguchi S: Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010, 11: 7-13. 10.1038/ni.1818.

Ying S: Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol. 2005, 174: 8183-8190.

Ying S: Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J Immunol. 2008, 181: 2790-2798.

Wilson MS: Suppression of murine allergic airway disease by IL-2: anti-IL-2 monoclonal antibody-induced regulatory T cells. J Immunol. 2008, 181: 6942-6954.

Lee CC, Lin SJ, Cheng PJ, Kuo ML: The regulatory function of umbilical cord blood CD4 CD25 T cells stimulated with anti-CD3/anti-CD28 and exogenous interleukin (IL)-2 or IL-15. Pediatr Allergy Immunol. 2009, 20 (7): 624-632(9). 10.1111/j.1399-3038.2008.00843.x.

Zeiser R: Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood. 2008, 111: 453-462. 10.1182/blood-2007-06-094482.

Jiang Q, Su H, Knudsen G, Helms W, Su L: Delayed functional maturation of natural regulatory T cells in the medulla of postnatal thymus: role of TSLP. BMC Immunol. 2006, 7: 6-10.1186/1471-2172-7-6.

Xystrakis E: Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest. 2006, 116: 146-155. 10.1172/JCI21759.

Nguyen KD, Vanichsarn C, Fohner A, Nadeau KC: Selective deregulation in chemokine signaling pathways of CD4+CD25(hi)CD127(lo)/(-) regulatory T cells in human allergic asthma. J Allergy Clin Immunol. 2009, 123: 933-939. 10.1016/j.jaci.2008.11.037.

Shi L: Local blockade of TSLP receptor alleviated allergic disease by regulating airway dendritic cells. Clin Immunol. 2008, 129: 202-210. 10.1016/j.clim.2008.07.015.

Knisz J: Loss of SOCS7 in mice results in severe cutaneous disease and increased mast cell activation. Clin Immunol. 2009, 132: 277-284. 10.1016/j.clim.2009.04.003.

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Allergy, Asthma & Clinical Immunology

Tập 6 Số 1

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