Distinct CD4⁺-T-Cell Responses to Live and Heat-InactivatedAspergillus fumigatusConidia

Abstract

Aspergillus fumigatus is an important fungal pathogen that causes invasive pulmonary disease in immunocompromised hosts. Respiratory exposure to A. fumigatus spores also causes allergic bronchopulmonary aspergillosis, a Th2 CD4؉ -T-cell-mediated disease that accompanies asthma. The microbial factors that influence the differentiation of A. fumigatus-specific CD4 ؉ T lymphocytes into Th1 versus Th2 cells remain incompletely defined. We therefore examined CD4؉ -T-cell responses of immunologically intact mice to intratracheal challenge with live or heat-inactivated A. fumigatus spores. Live but not heat-inactivated fungal spores resulted in recruitment of gamma interferon (IFN-␥)-producing, fungus-specific CD4؉ T cells to lung airways, achieving A. fumigatus-specific frequencies exceeding 5% of total CD4 ؉ T cells. While heat-inactivated spores did not induce detectable levels of IFN-␥-producing, A. fumigatus-specific CD4 ؉ T cells in the airways, they did prime CD4؉ T-cell responses in draining lymph nodes that produced greater amounts of interleukin 4 (IL-4) and IL-13 than T cells responding to live conidia. While immunization with live fungal spores induced antibody responses, we found a marked decrease in isotype-switched, A. fumigatus-specific antibodies in sera of mice following immunization with heat-inactivated spores. Our studies demonstrate that robust Th1 T-cell and humoral responses are restricted to challenge with fungal spores that have the potential to germinate and cause invasive infection. How the adaptive immune system distinguishes between metabolically active and inactive fungal spores remains an important question.

Expression of the surface antigens of lymphocytes and the levels of cytokines in mice infected with Aspergillus fumigatus

“…Rivera et al informed that Th 1 type cytokines were formed predominantly during the exposure to live conidia while the production of Th2 type cytokine was prominent following the immunization with heat inactivated conidia [13]. We observed that Th2 response was more prominent following the infection with live conidia.…”

“…Rivera et al also informed that humoral immune responses to A. fumigatus antigens mounted in mice infected with live but not heat-inactivated fungus [13].…”

“…Indeed, Rivera et al reported that CD4 T cells were not in high levels in the bronchoalveloar fluid of the mice infected with live and heat activated A. fumigatus conidia before the post infection day 7 and CD4 T cells were first detected only on the third day. Therefore, in our study, it is considered that there would be more CD4 cells if the mice were analyzed seven days after postinfection [13].…”

Dectin-1 and TLRs Permit Macrophages to Distinguish between Different Aspergillus fumigatus Cellular States

“…This finding may play a role in mediating adaptive responses to the fungus as well. Recently, Rivera et al (29) found that mice exposed to live A. fumigatus conidia develop Th1-biased CD4 ϩ T cell responses, whereas mice exposed to inactivated conidia demonstrate CD4 ϩ T cell responses that are more Th2 biased. The data suggest that differential recognition of conidia and hyphae can skew downstream adaptive immune responses.…”

Richness and diversity of mammalian fungal communities shape innate and adaptive immunity in health and disease

“…Cells producing IFN-γ are induced by Aspergillus in immunocompetent mice. Live conidia, which undergo swelling and germination, are able to prime Th1 responses [38] specific for C. albicans, Pneumocystis carinii, and Criptococcus spp. The observation that mice deficient in IL-17RA show an increased susceptibility to disseminated C. albicans infection first demonstrated the critical involvement of Th17 responses in protective anti-Candida host defenses [41].…”