Fungal infections can range from mild to severe and affect over a billion people worldwide. People whose immune systems have been compromised due to diseases such as AIDS or cancer, or patients who have been placed on immunosuppressive drugs after receiving stem cell or organ transplants, are more prone to opportunistic fungal infections. An intact immune system is capable of fending off fungal pathogens, therefore we wanted to further tease out the processes that an intact immune system uses to respond to fungi. The most well studied receptor that detects fungal cell wall components (β-glucans) is Dectin-1. We found that fungal β-glucan-stimulation of dendritic cells (DCs) enhanced antigen cross-presentation on MHCI molecules, up-regulated co-stimulatory molecules (CD40 and CD86) and induced pro-inflammatory cytokines (IL-2, IL-6, IL-12, TNF-α, and type I IFNs). Fungal β-glucans also stimulated DCs to induce strong CD8 T cell responses (up-regulation of activation markers CD44 and CD69, and production of IL-2, IFN-γ, TNF-α, and Granzyme B). Some of these responses were dependent on the autocrine action of type I IFNs on DCs, which promoted antigen cross-presentation on MHCI, expression of the co-stimulatory molecule CD86, and production of IL-2, TNF-α and IL- 6. CD8 T cell proliferation and production of IFN-γ and Granzyme B were also dependent on the effects of autocrine type I IFNs on DCs. These studies give us insight into how our immune systems normally respond to fungal infection in the context of Dectin-1 activation. This can provide us with clues about how to develop future therapeutics that promote more robust antifungal responses especially for patients whose immune systems are compromised.
|Commitee:||Goodridge, Helen, Lill, Michael, Martins, Gislaine, Pearlman, Eric, Underhill, David|
|School:||Cedars-Sinai Medical Center|
|Department:||Biomedical Science and Translational Medicine|
|School Location:||United States -- California|
|Source:||DAI-B 78/05(E), Dissertation Abstracts International|
|Keywords:||Dectin-1, Dendritic cells, Fungal glucans, T cell|
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