Vitamin D3 attenuates Th2 responses to Aspergillus fumigatus mounted by CD4+ T cells from cystic fibrosis patients with allergic bronchopulmonary aspergillosis.
Allergic bronchopulmonary aspergillosis (ABPA) is caused by a dominant Th2 immune response to antigens derived from the opportunistic mold Aspergillus, most commonly Aspergillus fumigatus. It occurs in 4%-15% of patients with cystic fibrosis (CF); however, not all patients with CF infected with A. fumigatus develop ABPA. Therefore, we compared cohorts of A. fumigatus-colonized CF patients with and without ABPA to identify factors mediating tolerance versus sensitization. We found that the costimulatory molecule OX40 ligand (OX40L) was critical in driving Th2 responses to A. fumigatus in peripheral CD4+ T cells isolated from patients with ABPA. In contrast, CD4+ T cells from the non-ABPA cohort did not mount enhanced Th2 responses in vitro and contained a higher frequency of TGF-beta-expressing regulatory T cells. Heightened Th2 reactivity in the ABPA cohort correlated with lower mean serum vitamin D levels. Further, in vitro addition of 1,25 OH-vitamin D3 substantially reduced DC expression of OX40L and increased DC expression of TGF-beta. This in vitro treatment also resulted in increased Treg TGF-beta expression and reduced Th2 responses by CD4+ T cells from patients with ABPA. These data provide rationale for a therapeutic trial of vitamin D to prevent or treat ABPA in patients with CF.
Kreindler
James L
JL
Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Steele
Chad
C
Nguyen
Nikki
N
Chan
Yvonne R
YR
Pilewski
Joseph M
JM
Alcorn
John F
JF
Vyas
Yatin M
YM
Aujla
Shean J
SJ
Finelli
Peter
P
Blanchard
Megan
M
Zeigler
Steven F
SF
Logar
Alison
A
Hartigan
Elizabeth
E
Kurs-Lasky
Marcia
M
Rockette
Howard
H
Ray
Anuradha
A
Kolls
Jay K
JK
D000328:Adult; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000276:immunology*; D001230:Aspergillus / Q000276:immunology; D001232:Aspergillus fumigatus / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002762:Cholecalciferol / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D053262:Receptors, OX40 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology
D053262:Receptors, OX40; C505716:TNFRSF4 protein, human; D016212:Transforming Growth Factor beta; D002762:Cholecalciferol