Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction
- 6 June 2019
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 4 (11)
- https://doi.org/10.1172/jci.insight.128241
Abstract
Despite the accepted notion that granulocytes play a universally destructive role in organ and tissue grafts, it has been recently described that eosinophils can facilitate immunosuppression-mediated acceptance of murine lung allografts. The mechanism of eosinophil-mediated tolerance, or their role in regulating alloimmune responses in the absence of immunosuppression, remains unknown. Using lung transplants in a fully MHC-mismatched BALB/c (H2d) to C57BL/6 (H2b) strain combination, we demonstrate that eosinophils downregulate T cell–mediated immune responses and play a tolerogenic role even in the absence of immunosuppression. We further show that such downregulation depends on PD-L1/PD-1–mediated synapse formation between eosinophils and T cells. We also demonstrate that eosinophils suppress T lymphocyte responses through the inhibition of T cell receptor/CD3 (TCR/CD3) subunit association and signal transduction in an inducible NOS–dependent manner. Increasing local eosinophil concentration, through administration of intratracheal eotaxin and IL-5, can ameliorate alloimmune responses in the lung allograft. Thus, our data indicate that eosinophil mobilization may be utilized as a novel means of lung allograft–specific immunosuppression.Keywords
Funding Information
- NIH (PO1 AI116501,R01 AI145108-01,R01 HL065228,R01 HL124165,R21 AI132840)
This publication has 51 references indexed in Scilit:
- A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1JCI Insight, 2012
- Eosinophils Regulate Dendritic Cells and Th2 Pulmonary Immune Responses following Allergen ProvocationThe Journal of Immunology, 2011
- T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouseThe Journal of Experimental Medicine, 2011
- Mechanism of T Cell Tolerance Induced by Myeloid-Derived Suppressor CellsPublished by The American Association of Immunologists ,2010
- Inhaled Cyclosporine and Pulmonary Function in Lung Transplant RecipientsJournal of Aerosol Medicine and Pulmonary Drug Delivery, 2010
- Mechanisms of costimulationImmunological Reviews, 2009
- Donor-Reactive CD8 Memory T Cells Infiltrate Cardiac Allografts Within 24-h Posttransplant in Naive RecipientsAmerican Journal of Transplantation, 2008
- Allergic pulmonary inflammation in mice is dependent on eosinophil-induced recruitment of effector T cellsThe Journal of Experimental Medicine, 2008
- Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancerNature Medicine, 2007
- High-Sensitivity Detection and Quantitative Analysis of Native Protein-Protein Interactions and Multiprotein Complexes by Flow CytometryScience's STKE, 2007