Blockade of CTLA-4 enhances allergic sensitization and eosinophilic airway inflammation in genetically predisposed mice

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Abstract
CTLA‐4 (CD152) expression is restricted to subsets of activated T lymphocytes and shares homology with CD28. CTLA‐4 and CD28 molecules both bind to B7 molecules on antigen‐presenting cells. Whereas CD28‐B7 interaction enhances T cell activation, cytokine production and survival, CTLA‐4 signaling down‐regulates T cell responses. Here, we studied the involvement of CTLA‐4 triggering in thepathogenesis of allergen‐induced airway inflammation in mice. Anti‐CTLA‐4 mAb were injected during i.p. sensitization with ovalbumin (OVA). This treatment favored OVA‐specific IgE production and augmented blood eosinophilia in BALB/c mice. In BALB/c mice, enhanced Th2 sensitization after anti‐CTLA‐4 mAb injections resulted in more severe airway inflammation, and increased airway hyperresponsiveness to metacholine, bronchial eosinophilia and IL‐4 and IL‐5 levels in broncho‐alveolar lavage (BAL) fluid following repeated allergen inhalations. Importantly, aggravation of airway inflammationand enhancement of Th2 responses were accompanied by a significant reduction of pulmonary TGF‐β levels at protein level in BAL fluid as well as on mRNA level in inflamed lung tissue. In contrast to BALB/c mice, blockade of CTLA‐4 did not alter IgE production nor the phenotype of airway inflammation or TGF‐β production in C57BL/6 mice. Our data suggest that CTLA‐4 triggering represents an important regulatory mechanism for Th2 sensitization in genetically predisposed mice by modulating TGF‐β production.