Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung

Journal of Immunology - Tập 184 Số 8 - Trang 4414-4422 - 2010
Yuko Yoshida1,2, Masayuki Umemura1,2, Ayano Yahagi1,2, Rebecca L. O’Brien3, Koichi Ikuta4, Kenji Kishihara5, Hiromitsu Hara6, Susumu Nakae7, Yoichiro Iwakura8, Goro Matsuzaki1,2
1*Tropical Biosphere Research Center and
2†Division of Host Defense and Vaccinology, Department of Microbiology, Graduate School of Medicine, University of the Ryukyus, Okinawa;
3*Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80206;
4§Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto;
5¶Division of Immunology, Department of Pharmacy, Faculty of Pharmaceutical Sciences, Nagasaki International University, Nagasaki;
6‖Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga;
7#Frontier Research Initiative and
8**Center for Experimental Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; and

Tóm tắt

Abstract Granulomas play an essential role in the sequestration and killing of mycobacteria in the lung; however, the mechanisms of their development and maturation are still not clearly understood. IL-17A is involved in mature granuloma formation in the mycobacteria-infected lung. Therefore, IL-17A gene-knockout (KO) mice fail to develop mature granulomas in the Mycobacterium bovis bacille Calmette-Guérin (BCG)-infected lung. This study analyzed the mechanism of IL-17A–dependent mature granuloma formation in the mycobacteria-infected lung. The IL-17A KO mice showed a normal level of nascent granuloma formation on day 14 but failed to develop mature granulomas on day 28 after the BCG infection in the lung. The observation implies that IL-17A is required for the maturation of granuloma from the nascent to mature stage. TCR γδ T cells expressing TCR Vγ4 or Vγ6 were identified as the major IL-17A–producing cells that resided in the BCG-induced lung granuloma. The adoptive transfer of the IL-17A–producing TCR γδ T cells reconstituted granuloma formation in the IL-17A KO mice. The expression of ICAM-1 and LFA-1, which are adhesion molecules important in granuloma formation, decreased in the lung of the BCG-infected IL-17A KO mice, and their expression was induced on BCG-infected macrophages in coculture with IL-17A–producing TCR γδ T cells. Furthermore, IL-17A KO mice showed not only an impaired mature granuloma formation, but also an impaired protective response to virulent Mycobacterium tuberculosis. Therefore, IL-17A produced by TCR γδ T cells plays a critical role in the prevention of M. tuberculosis infection through the induction of mature granuloma formation.

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Journal of Immunology

Tập 184 Số 8

4414-4422

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