Long-lived regulatory T cells generated during severe bronchiolitis in infancy influence later progression to asthma
| Autor: | Simon Phipps, Jason P. Lynch, Ridwan B. Rashid, Ismail Sebina, Md. Al Amin Sikder, Vivian Zhang, Geoff R. Hill, John W. Upham, Raymond J. Steptoe, Bodie F. Curren, Ashik Ullah, Rhiannon B. Werder |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adoptive cell transfer Regulatory T cell Immunology chemical and pharmacologic phenomena Inflammation Plasmacytoid dendritic cell HMGB1 Severity of Illness Index T-Lymphocytes Regulatory 03 medical and health sciences Mice 0302 clinical medicine T-Lymphocyte Subsets medicine Immunology and Allergy Animals Ectonucleotidase HMGB1 Protein Asthma biology business.industry hemic and immune systems Allergens medicine.disease respiratory tract diseases Disease Models Animal Protein Transport 030104 developmental biology medicine.anatomical_structure Bronchiolitis biology.protein Disease Progression Cytokines Immunization Disease Susceptibility medicine.symptom business Biomarkers 030215 immunology |
| Zdroj: | Mucosal immunology. 13(4) |
| ISSN: | 1935-3456 |
| Popis: | The type-2 inflammatory response that promotes asthma pathophysiology occurs in the absence of sufficient immunoregulation. Impaired regulatory T cell (Treg) function also predisposes to severe viral bronchiolitis in infancy, a major risk factor for asthma. Hence, we hypothesized that long-lived, aberrantly programmed Tregs causally link viral bronchiolitis with later asthma. Here we found that transient plasmacytoid dendritic cell (pDC) depletion during viral infection in early-life, which causes the expansion of aberrant Tregs, predisposes to allergen-induced or virus-induced asthma in later-life, and is associated with altered airway epithelial cell (AEC) responses and the expansion of impaired, long-lived Tregs. Critically, the adoptive transfer of aberrant Tregs (unlike healthy Tregs) to asthma-susceptible mice failed to prevent the development of viral-induced or allergen-induced asthma. Lack of protection was associated with increased airway epithelial cytoplasmic-HMGB1 (high-mobility group box 1), a pro-type-2 inflammatory alarmin, and granulocytic inflammation. Aberrant Tregs expressed lower levels of CD39, an ectonucleotidase that hydrolyzes extracellular ATP, a known inducer of alarmin release. Using cultured mouse AECs, we identify that healthy Tregs suppress allergen-induced HMGB1 translocation whereas this ability is markedly impaired in aberrant Tregs. Thus, defective Treg programming in infancy has durable consequences that underlie the association between bronchiolitis and subsequent asthma. |
| Databáze: | OpenAIRE |
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