Sensitization of CD4⁺ T cells to innocuous antigens results in adverse hypersensitivity responses upon re-exposure to the antigens. In the lung, chronic hypersensitivity responses to inhaled antigens result in the immunopathogenesis of various diseases. The ubiquitous fungus Aspergillus fumigatus releases airborne conidia and is associated with several pulmonary hypersensitivity diseases. We hypothesized that repeated inhalation of A. fumigatus conidia will result in a CD4 ⁺ T cell-mediated hypersensitivity response that promotes pathological alterations in lung structure and function.

Viable A. fumigatus conidia (2×10⁶) were administered to C57BL/6 mice via the intranasal route every week for a variable number of total exposures. In a CD4⁺ T cell-independent manner, the innate immune response prevented growth of inhaled conidia. In a CD⁺ T cell-dependent manner, a significant increase in airway lymphocytes and eosinophils resulted from several exposures to conidia. Thus, repeated inhalation of conidia resulted in a CD4⁺ T cell-mediated hypersensitivity response out of proportion to the fungal burden.

The chronic hypersensitivity response to A. fumigatus did not result in progressive airway remodeling but did result in severe, progressive remodeling of pulmonary arteries reminiscent of the primary abnormality found in patients with pulmonary arterial hypertension. The lumens of small-to-medium sized pulmonary arteries were significantly narrowed, and the remodeled arterial walls were muscularized, fibrotic, and exhibited signs of neointimal formation. CD4⁺ T cells were required for the full manifestation of pulmonary inflammation and arterial remodeling, but some degree of CD4⁺ T cell-independent luminal narrowing was noted. Arterial remodeling developed in mice deficient for IFNγ, the critical T_H1 effector cytokine, but not in mice deficient for IL-4, a critical cytokine for the manifestation of T_H2 responses. IL-10-deficient mice did not develop CD4 ⁺ T_H2 cells, airway eosinophilia, or arterial remodeling. Based on results from the study of IL-5-deficient mice, the T_H2-mediated pathogenesis of arterial remodeling did not require eosinophils. Though mice developed severe arterial muscularization, arterial fibrosis, and significant luminal narrowing, mice did not develop pulmonary hypertension as a result. Along with several recent reports, these data support a novel mechanism for the pathogenesis of pulmonary arterial remodeling.