CD103 integrin identifies a high IL-10-producing FoxP3+ regulatory T
cell population suppressing allergic airway inflammation
Abstract
Background: Although FoxP3+ regulatory T (Treg) cells constitute a
highly heterogeneous population, with different regulatory potential
depending on the context, distinct subsets or phenotypes remain poorly
defined. This hampers the development of immunotherapy for allergic and
autoimmune disorders. This study aimed at characterizing distinct FoxP3+
Treg subpopulations involved in the suppression of Th2-mediated allergic
inflammation in the lung. Methods: We used an established mouse model of
allergic airway disease based on ovalbumin sensitization and challenge
to analyze FoxP3+ Tregs during the induction and resolution of
inflammation, and identify markers that distinguish their most
suppressive phenotypes. We also developed a new knock-in mouse model
(Foxp3creCd103dtr) enabling the specific ablation of CD103+FoxP3+ Tregs
for functional studies. Results: We found that during resolution of
allergic airway inflammation in mice >50% of FoxP3+ Treg
cells expressed the integrin CD103 which marks FoxP3+ Treg cells of high
IL-10 production, increased expression of immunoregulatory molecules
such as KLRG1, ICOS and CD127, and enhanced suppressive capacity for
Th2-mediated inflammatory responses. CD103+FoxP3+ Tregs were essential
for keeping allergic inflammation under control as their specific
depletion in Foxp3creCd103dtr mice lead to severe alveocapillary damage
and eosinophilic pneumonia, markedly reducing the lifespan of the
experimental animals. Conversely, adoptive transfer of CD103+FoxP3+
Tregs effectively treated disease, attenuating Th2 responses and
allergic inflammation in an IL-10-dependent manner. Conclusion: Our
study identifies a novel regulatory T cell population, defined by CD103
expression, programmed to prevent exuberant type 2 inflammation and keep
homeostasis in the respiratory tract under control. This has important
therapeutic implications.