Serial OX40 engagement on CD4+ T cells and natural killer T cells causes allergic airway inflammation.
BACKGROUND
OX40-OX40 ligand (OX40L) interactions have been proposed to support induction of allergic airway inflammation, which may be attributable to OX40 signaling in CD4(+) helper T cells for adaptive immune responses. However, a possible involvement of natural killer T (NKT) cells in the pathogenesis suggests that the underlying mechanisms are not yet fully elucidated.


OBJECTIVE
We aimed to characterize the OX40-modulated cellular contribution to allergic airway inflammation in a mouse model of house dust mite (HDM) allergen exposure.


METHODS
Mice were sensitized to HDM and, 3 weeks later, challenged with HDM on three consecutive days through the airways. Two days after the last exposure, bronchoalveolar lavage fluids and blood samples and lung tissues were evaluated for the airway inflammation.


RESULTS
The development of HDM-induced eosinophilic airway inflammation was dependent on OX40 of both CD4(+) T cells and NKT cells; OX40 engagement on CD4(+) T cells in the sensitization led to pulmonary OX40L augmentation after the allergen challenge, which stimulated pulmonary NKT cells through OX40 to provide the pathogenic cytokine milieu. This was ablated by OX40L blockade by inhalation of the neutralizing antibody during the challenge, suggesting the therapeutic potential of targeting pulmonary OX40-OX40L interactions. Moreover, OX40 expression in CD4(+) T cells, but not in NKT cells, was reciprocally regulated by the helper T cell type 1-skewing transcription factor Runx3.


CONCLUSIONS
OX40 on not only CD4(+) T cells but also NKT cells is involved in allergic airway inflammation. Notably, pulmonary blockade of OX40 ligation on NKT cells has therapeutic implications.
Damayanti
Triya
T
Department of Pulmonary Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Kikuchi
Toshiaki
T
Zaini
Jamal
J
Daito
Hisayoshi
H
Kanehira
Masahiko
M
Kohu
Kazuyoshi
K
Ishii
Naoto
N
Satake
Masanobu
M
Sugamura
Kazuo
K
Nukiwa
Toshihiro
T
D000485:Allergens / Q000276:immunology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D008168:Lung / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology*; D053278:OX40 Ligand / Q000276:immunology*; D039981:Pyroglyphidae / Q000276:immunology; D053262:Receptors, OX40 / Q000276:immunology*
D000485:Allergens; D053278:OX40 Ligand; D053262:Receptors, OX40