Background. Thymic stromal lymphopoietin (TSLP) is induced in allergic skin and lung inflammation in man and mice. Methods. Allergic lung inflammation induced by two proteases allergens HDM and papain and a classical allergen ovalbumin was evaluated in vivo in mice deficient for TSLPR. Eosinophil recruitment, Th2 and Th17 cytokine and chemokine levels were determined in bronchoalveolar lavage fluid, lung homogenates and lung mononuclear cells ex vivo. Results. Here we report that mice challenged with house dust mite extract or papain in the absence of TSLPR have a drastic reduction of allergic inflammation with diminished eosinophil recruitment in BAL and lung and reduced mucus overproduction. TSLPR deficient DCs displayed diminished OVA antigen uptake and reduced capacity to activate antigen specific T cells. TSLPR deficient mice had diminished proinflammatory IL-1β, IL-13, and IL-33 chemokines production, while IL-17A, IL-12p40 and IL-10 were increased. Together with impaired Th2 cytokines, IL-17A expressing TCRβ+ T cells were increased, while IL-22 expressing CD4+ T cells were diminished in the lung. Conclusion. Therefore, TSLPR signaling is required for the development of both Th2 and Th22 responses and may restrain IL-17A. TSLP may mediate its effects in part by increasing allergen uptake and processing by DCs resulting in an exacerbated asthma. 1. Introduction The allergic inflammatory response is characterized by a predominant Th2-cell pathway, which is initiated by the uptake of allergens by professional antigen presenting cells (APCs) that present selected peptides on MHC class II molecules to naive T cells, together with isotype switching of B cells to generate IgE antibodies specific for common environmental allergens [1]. The cytokines associated with Th2 response are IL-4, IL-5, IL-9, IL-13, and IL-33 [2, 3]. Thymic stromal lymphopoietin (TSLP) was first identified as a growth-promoting factor produced by mouse thymic stromal cells that supported the development of immature B cells to the B220+/IgM+ stage [4]. TSLP is a type I cytokine that acts via the heteromeric receptor consisting of IL-7Rα and a TSLP-specific subunit, TSLP receptor (TSLPR) [5, 6] signaling via JAK1 and JAK2 to mediate the activation of STAT5A and STAT5B [7]. TSLPR has homology to the common cytokine receptor -chain, , a component of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 [8]. TSLP is expressed by a range of cell types, including epithelial cells, fibroblasts, keratinocytes, mast cells, protease-activated basophils, human CD68+ macrophages, and
References
[1]
M. Wills-Karp, “Immunologic basis of antigen-induced airway hyperresponsiveness,” Annual Review of Immunology, vol. 17, pp. 255–281, 1999.
[2]
F. D. Finkelman, S. P. Hogan, G. K. Khurana Hershey, M. E. Rothenberg, and M. Wills-Karp, “Importance of cytokines in murine allergic airway disease and human asthma,” Journal of Immunology, vol. 184, no. 4, pp. 1663–1674, 2010.
[3]
A. Soussi-Gounni, M. Kontolemos, and Q. Hamid, “Role of IL-9 in the pathophysiology of allergic diseases,” Journal of Allergy and Clinical Immunology, vol. 107, no. 4, pp. 575–582, 2001.
[4]
S. L. Friend, S. Hosier, A. Nelson, D. Foxworthe, D. E. Williams, and A. Farr, “A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells,” Experimental Hematology, vol. 22, no. 3, pp. 321–328, 1994.
[5]
A. Pandey, K. Ozaki, H. Baumann et al., “Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin,” Nature Immunology, vol. 1, no. 1, pp. 59–64, 2000.
[6]
L. S. Park, U. Martin, K. Garka et al., “Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: formation of a functional heteromeric complex requires interleukin 7 receptor,” Journal of Experimental Medicine, vol. 192, no. 5, pp. 659–670, 2000.
[7]
Y. Rochman, M. Kashyap, G. W. Robinson et al., “Thymic stromal lymphopoietin-mediated STAT5 phosphorylation via kinases JAK1 and JAK2 reveals a key difference from IL-7-induced signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 45, pp. 19455–19460, 2010.
[8]
W. J. Leonard, “Cytokines and immunodeficiency diseases,” Nature Reviews Immunology, vol. 1, no. 3, pp. 200–208, 2001.
[9]
V. Soumelis, P. A. Reche, H. Kanzler et al., “Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLP,” Nature Immunology, vol. 3, no. 7, pp. 673–680, 2002.
[10]
S. Ying, B. O'Connor, J. Ratoff et al., “Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease,” Journal of Immunology, vol. 181, no. 4, pp. 2790–2798, 2008.
[11]
A. Al-Shami, R. Spolski, J. Kelly et al., “A role for thymic stromal lymphopoietin in CD4+ T cell development,” Journal of Experimental Medicine, vol. 200, no. 2, pp. 159–168, 2004.
[12]
I. Rochman, N. Watanabe, K. Arima, Y. J. Liu, and W. J. Leonard, “Cutting edge: direct action of thymic stromal lymphopoietin on activated human CD4+ T cells,” Journal of Immunology, vol. 178, no. 11, pp. 6720–6724, 2007.
[13]
Z. Allakhverdi, M. R. Comeau, H. K. Jessup et al., “Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells,” Journal of Experimental Medicine, vol. 204, no. 2, pp. 253–258, 2007.
[14]
Y. Nagata, H. Kamijuku, M. Taniguchi, S. Ziegler, and K. I. Seino, “Differential role of thymic stromal lymphopoietin in the induction of airway hyperreactivity and Th2 immune response in antigen-induced asthma with respect to natural killer T cell function,” International Archives of Allergy and Immunology, vol. 144, no. 4, pp. 305–314, 2007.
[15]
C. K. Wong, S. Hu, P. F. Y. Cheung, and C. W. K. Lam, “Thymic stromal lymphopoietin induces chemotactic and prosurvival effects in eosinophils: implications in allergic inflammation,” American Journal of Respiratory Cell and Molecular Biology, vol. 43, no. 3, pp. 305–315, 2010.
[16]
S. F. Ziegler and Y. J. Liu, “Thymic stromal lymphopoietin in normal and pathogenic T cell development and function,” Nature Immunology, vol. 7, no. 7, pp. 709–714, 2006.
[17]
Y. Rochman and W. J. Leonard, “The role of thymic stromal lymphopoietin in CD8+ T cell homeostasis,” Journal of Immunology, vol. 181, no. 11, pp. 7699–7705, 2008.
[18]
Y. Rochman and W. J. Leonard, “Thymic stromal lymphopoietin: a new cytokine in asthma,” Current Opinion in Pharmacology, vol. 8, no. 3, pp. 249–254, 2008.
[19]
S. F. Ziegler, “The role of thymic stromal lymphopoietin (TSLP) in allergic disorders,” Current Opinion in Immunology, vol. 22, no. 6, pp. 795–799, 2010.
[20]
H. Hammad, M. Chieppa, F. Perros, M. A. Willart, R. N. Germain, and B. N. Lambrecht, “House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells,” Nature Medicine, vol. 15, no. 4, pp. 410–416, 2009.
[21]
C. L. Sokol, G. M. Barton, A. G. Farr, and R. Medzhitov, “A mechanism for the initiation of allergen-induced T helper type 2 responses,” Nature Immunology, vol. 9, no. 3, pp. 310–318, 2008.
[22]
T. Y. Halim, R. H. Krauss, A. C. Sun, and F. Takei, “Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation,” Immunity, vol. 36, pp. 451–463, 2012.
[23]
A. J. M. Van Oosterhout, D. Fattah, I. Van Ark, G. Hofman, T. L. Buckley, and F. P. Nijkamp, “Eosinophil infiltration precedes development of airway hyperreactivity and mucosal exudation after intranasal administration of interleukin-5 to mice,” Journal of Allergy and Clinical Immunology, vol. 96, no. 1, pp. 104–112, 1995.
[24]
P. Hachem, M. Lisbonne, M. L. Michel et al., “α-galactosylceramide-induced iNKT cells suppress experimental allergic asthma in sensitized mice: role in IFN-γ,” European Journal of Immunology, vol. 35, no. 10, pp. 2793–2802, 2005.
[25]
J. R. Johnson, R. E. Wiley, R. Fattouh et al., “Continuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling,” American Journal of Respiratory and Critical Care Medicine, vol. 169, no. 3, pp. 378–385, 2004.
[26]
A. Trompette, S. Divanovic, A. Visintin et al., “Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein,” Nature, vol. 457, no. 7229, pp. 585–588, 2009.
[27]
L. Chambers, A. Brown, D. I. Pritchard, S. Sreedharan, K. Brocklehurst, and N. A. Kalsheker, “Enzymatically active papain preferentially induces an allergic response in mice,” Biochemical and Biophysical Research Communications, vol. 253, no. 3, pp. 837–840, 1998.
[28]
K. Oboki, T. Ohno, N. Kajiwara et al., “IL-33 is a crucial amplifier of innate rather than acquired immunity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, pp. 18581–18586, 2010.
[29]
M. Kashyap, Y. Rochman, R. Spolski, L. Samsel, and W. J. Leonard, “Thymic stromal lymphopoietin is produced by dendritic cells,” The Journal of Immunology, vol. 187, pp. 1207–1211, 2011.
[30]
S. Lajoie, I. P. Lewkowich, Y. Suzuki et al., “Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma,” Nature Immunology, vol. 11, no. 10, pp. 928–935, 2010.
[31]
Y. H. Wang and M. Wills-Karp, “The potential role of interleukin-17 in severe asthma,” Current Allergy and Asthma Reports, vol. 11, no. 5, pp. 388–394, 2011.
[32]
B. Schnyder, S. Schnyder-Candrian, A. Pansky et al., “IL-17 reduces TNF-induced Rantes and VCAM-1 expression,” Cytokine, vol. 31, no. 3, pp. 191–202, 2005.
[33]
S. Schnyder-Candrian, D. Togbe, I. Couillin et al., “Interleukin-17 is a negative regulator of established allergic asthma,” Journal of Experimental Medicine, vol. 203, no. 12, pp. 2715–2725, 2006.
[34]
A. G. Besnard, R. Sabat, L. Dumoutier et al., “Dual Role of IL-22 in allergic airway inflammation and its cross-talk with IL-17A,” American Journal of Respiratory and Critical Care Medicine, vol. 183, no. 9, pp. 1153–1163, 2011.
[35]
C. Taube, C. Tertilt, G. Gyulveszi et al., “IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease,” PLoS ONE, vol. 6, Article ID e21799, 2011.
[36]
Y. J. Liu, “Thymic stromal lymphopoietin: master switch for allergic inflammation,” Journal of Experimental Medicine, vol. 203, no. 2, pp. 269–273, 2006.
[37]
H. J. De Heer, H. Hammad, T. Soullié et al., “Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen,” Journal of Experimental Medicine, vol. 200, no. 1, pp. 89–98, 2004.
[38]
H. Hammad and B. N. Lambrecht, “Dendritic cells and airway epithelial cells at the interface between innate and adaptive immune responses,” Allergy, vol. 66, no. 5, pp. 579–587, 2011.
[39]
A. Joetham, K. Takeda, C. Taube et al., “Naturally occurring lung CD4+CD25+ T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta,” Journal of Immunology, vol. 178, pp. 1433–1442, 2007.
[40]
J. Kearley, J. E. Barker, D. S. Robinson, and C. M. Lloyd, “Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent,” Journal of Experimental Medicine, vol. 202, no. 11, pp. 1539–1547, 2005.
[41]
A. O'Garra, F. J. Barrat, A. G. Castro, A. Vicari, and C. Hawrylowicz, “Strategies for use of IL-10 or its antagonists in human disease,” Immunological Reviews, vol. 223, no. 1, pp. 114–131, 2008.
[42]
S. J. Till, J. N. Francis, K. Nouri-Aria, and S. R. Durham, “Mechanisms of immunotherapy,” Journal of Allergy and Clinical Immunology, vol. 113, no. 6, pp. 1025–1035, 2004.
[43]
Y. J. Liu, V. Soumelis, N. Watanabe et al., “TSLP: an epithelial cell cytokine that regulates t cell differentiation by conditioning dendritic cell maturation,” Annual Review of Immunology, vol. 25, pp. 193–219, 2007.
[44]
S. F. Ziegler and D. Artis, “Sensing the outside world: TSLP regulates barrier immunity,” Nature Immunology, vol. 11, no. 4, pp. 289–293, 2010.
[45]
M. Wills-Karp and F. D. Finkelman, “Innate lymphoid cells wield a double-edged sword,” Nature Immunology, vol. 12, pp. 1025–1027, 2011.
[46]
J. S. Lee, M. Cella, K. G. McDonald et al., “AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch,” Nature Immunology, vol. 13, no. 2, pp. 144–151, 2012.
