Abstract
Type 2 helper T cells (TH2) are critically involved in allergies and asthma. Here we demonstrate that extracellular matrix protein-1 (ECM1) is highly and selectively expressed in TH2 cells. ECM1 deficiency caused impaired TH2 responses and reduced allergic airway inflammation in vivo. Functional analysis demonstrated that although the TH2 polarization of ECM1-deficient cells was unimpaired, these cells had a defect in migration and were retained in peripheral lymphoid organs. This was associated with reduced expression of KLF2 and S1P1. We also found that ECM1 could directly bind the interleukin-2 (IL-2) receptor to inhibit IL-2 signaling and activate S1P1 expression. Our data identify a previously unknown function of ECM1 in regulating TH2 cell migration through control of KLF2 and S1P1 expression.
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Acknowledgements
We thank R. Caspi, Y. He, Y. Zhuang, H. Gu, W. Zhang, Y. Liu and D. Li for helpful comments about this paper, S. Skinner for reviewing the manuscript, and X. Zhu for help with the experiments. This work was supported by grants from the National Natural Science Foundation of China (30623003, 31030029, 30721065, 30801011, 90713044, 30870126, 30950002), a Chinese Academy of Sciences project (KSCX2-YW-R-161, KSCX2-YW-R-169), the Technology Commission of Shanghai Municipality (08DZ2291703, 088014199, 08431903004), the National 973 key project (2007CB512404), the National 863 project (2006AA02A247), an EU project (SP5B-CT-2006-044161), a China National Science and Technology Major Project (2008ZX10002-014, 2008ZX10004-002, 2009ZX10004-105, 2009ZX10004-016), the China National Ministry of Science and Technology (20072714), the Shanghai Pasteur Health Research Foundation (SPHRF2008001, SPHRF2009001), the E-institutes of the Shanghai Universities Immunology Division and the Li Kha Shing Foundation.
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Z. Li designed (with help from Z. Liu) and performed mouse experiments and in vitro cell culture experiments, analyzed data and wrote the manuscript; Y. Zhang did all western blotting and real-time PCR experiments and helped in mouse experiments and analyzing data; X.W., K.M. and Y. Zheng helped in mouse experiments; Z.T. bred mice and confirmed the Ecm1−/− genotype; J.W. helped with immunoprecipitation experiments; G.L., L.T. and Y.J. made two ECM1 antibodies; M.Q. supplied reagents; S.S. performed flow cytometry; X.Z. helped design experiments and edit the manuscript; and B.S. conceived of the research, directed the study and edited the manuscript.
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Li, Z., Zhang, Y., Liu, Z. et al. ECM1 controls TH2 cell egress from lymph nodes through re-expression of S1P1. Nat Immunol 12, 178–185 (2011). https://doi.org/10.1038/ni.1983
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DOI: https://doi.org/10.1038/ni.1983
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