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Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO

Cellular & Molecular Immunology volume 7, pages 459–470 (2010)Cite this article

Abstract

Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance. Whereas the pivotal role of dendritic cells in determining the balance between immunopathology and protective immunity to the fungus is well established, we determined that epithelial cells (ECs) also contributes to this balance. Mechanistically, EC-mediated protection occurred through a Toll-like receptor 3/Toll/IL-1 receptor domain-containing adaptor-inducing interferon (TLR3/TRIF)-dependent pathway converging on indoleamine 2,3-dioxygenase (IDO) via non-canonical nuclear factor-κB activation. Consistent with the high susceptibility of TRIF-deficient mice to pulmonary aspergillosis, bone marrow chimeric mice with TRIF unresponsive ECs exhibited higher fungal burdens and inflammatory pathology than control mice, underexpressed the IDO-dependent T helper 1/regulatory T cell (Th1/Treg) pathway and overexpressed the Th17 pathway with massive neutrophilic inflammation in the lungs. Further studies with interferon (IFN)-γ, IDO or IL-17R unresponsive cells confirmed the dependency of immune tolerance to the fungus on the IFN-γ/IDO/Treg pathway and of immune resistance on the MyD88 pathway controlling the fungal growth. Thus, distinct immune pathways contribute to resistance and tolerance to the fungus, to which the hematopoietic/non-hematopoietic compartments contribute through distinct, yet complementary, roles.

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Acknowledgements

We thank Cristina Massi Benedetti for digital art and editing. This work was supported by the Specific Targeted Research Project ‘Sybaris’ (LSHE-CT-2006), contract number 037899 (FP7) and by the Italian Projects PRIN 2007KLCKP8_004 (to LR) and 2007XYB9T9_001 (to SB). CC and AC were financially supported by fellowships from Fundação para a Ciência e Tecnologia, Portugal (contracts SFRH/BD/65962/2009 and SFRH/BPD/46292/2008, respectively).

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Authors and Affiliations

  1. Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy

    Antonella de Luca, Silvia Bozza, Teresa Zelante, Silvia Zagarella, Carmen D'Angelo, Katia Perruccio, Carmine Vacca, Agostinho Carvalho, Cristina Cunha, Franco Aversa & Luigina Romani

  2. Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal

    Agostinho Carvalho

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  1. Antonella de Luca
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  2. Silvia Bozza
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Correspondence to Luigina Romani.

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de Luca, A., Bozza, S., Zelante, T. et al. Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO. Cell Mol Immunol 7, 459–470 (2010). https://doi.org/10.1038/cmi.2010.43

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