Coevolution of T_H1, T_H2, and T_H17 Responses during Repeated Pulmonary Exposure toAspergillus fumigatusConidia

Abstract

Aspergillus fumigatus, a ubiquitous airborne fungus, can cause invasive infection in immunocompromised individuals but also triggers allergic bronchopulmonary aspergillosis in a subset of otherwise healthy individuals repeatedly exposed to the organism. This study addresses a critical gap in our understanding of the immunoregulation in response to repeated exposure to A. fumigatus conidia. C57BL/6 mice were challenged intranasally with A. fumigatus conidia weekly, and leukocyte composition, activation, and cytokine production were examined after two, four, and eight challenges. Approximately 99% of A. fumigatus conidia were cleared within 24 h after inoculation, and repeated exposure to A. fumigatus conidia did not result in hyphal growth or accumulation of conidia with time. After 2 challenges, there was an early influx of neutrophils and regulatory T (T reg ) cells into the lungs but minimal inflammation. Repeated exposure promoted sustained expansion of the draining lymph nodes, while the influx of eosinophils and other myeloid cells into the lungs peaked after four exposures and then decreased despite continued A. fumigatus challenges. Goblet cell metaplasia and low-level fibrosis were evident during the response. Repeated exposure to A. fumigatus conidia induced T cell activation in the lungs and the codevelopment by four exposures of T H 1, T H 2, and T H 17 responses in the lungs, which were maintained through eight exposures. Changes in CD4 T cell polarization or T reg numbers did not account for the reduction in myeloid cell numbers later in the response, suggesting a non-T-cell regulatory pathway involved in dampening inflammation during repeated exposure to A. fumigatus conidia.

The Role of Regulatory T Cells in the Regulation of Upper Airway Inflammation

“…[76][77][78] Although studies in mice found that a single exposure to A. fumagatis induced increases in Treg numbers and function in the lung, repeated exposure models, more akin to the exposure humans experience, was found to shift T-cell responses toward a pathogenic Th2-Th17 phenotype. 79 The secosteroid hormone 1,25-dihydroxyvitamin D3 (1,25[OH]D 3 ) has been shown in multiple disease states to induce Tregs. [80][81][82][83][84][85] However, patients with CRSwNP have reduced sinonasal levels of 1,25(OH)D 3 compared with controls or those with CRSsNP.…”

B lymphocytes regulate airway granulocytic inflammation and cytokine production in a murine model of fungal allergic asthma

“…IL-6 also promotes inflammation and pulmonary fibrosis, 41,56 suggesting that the 'Th2 theory' is probably inadequate to explain the diverse forms of asthma in humans and the various inflammatory responses observed in animal models of allergic asthma. 12,57,58 In recent years, a number of research groups have demonstrated a more direct role for IL-17 in exacerbating eosinophilia and neutrophilia. 12,[58][59][60] Similarly, the neutralization of IL-6 has been associated with decreased inflammation in allergic mice, and this phenomenon occurs in conjunction with IL-17A, indicating that IL-6 regulates IL-17A production in models of lung injury.…”

“…12,57,58 In recent years, a number of research groups have demonstrated a more direct role for IL-17 in exacerbating eosinophilia and neutrophilia. 12,[58][59][60] Similarly, the neutralization of IL-6 has been associated with decreased inflammation in allergic mice, and this phenomenon occurs in conjunction with IL-17A, indicating that IL-6 regulates IL-17A production in models of lung injury. 41 Consistent with these observations, we also observed an increased IL-17 and IL-6 response in the absence of B lymphocytes in J H 2/2 mice.…”

“…2,7,8 The hallmarks of chronic airway inflammation in patients with severe or persistent fungal asthma include the accumulation of activated eosinophils, 9-11 neutrophils, 12,13 lymphocytes 12,14 and ECM components. 15,16 To recapitulate many of the acute and chronic features of clinical fungal asthma, we developed an Aspergillus fumigatus experimental model in which sensitization of mice with fungal extracts is followed by allergy challenge with inhaled Aspergillus conidia.…”

Evolution of CD4+CD25hi T cell subsets in Aspergillus-infected liver transplantation recipients reduces the incidence of transplantation rejection via upregulating the production of anti-inflammatory cytokines

“…Both Th1, Th2, and Th17 responses in mice were shown to evolve during repeated pulmonary exposure to Aspergillus (Murdock et al, 2011). Treg cells involved in the development of aspergillosis provide the host with adequate defense without necessarily eliminating the fungus or causing unacceptable levels of host damage (Montagnoli et al, 2006).…”