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Chapter 21 : CD4+ T-Cell Responses to Aspergillus fumigatus
Category: Clinical Microbiology; Fungi and Fungal Pathogenesis
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This chapter reviews recent advances in understanding Aspergillus fumigatus-specific CD4+ T-cell activation and differentiation. Repeated exposure to fungal antigens is inconsequential in most individuals, due primarily to the rapid induction of antimicrobial defenses by innate immune cells of the airways. In some susceptible individuals, however, a variety of allergic responses to A. fumigatus, including allergic rhinitis, allergic sinusitis, and allergic asthma, can ensue. It has been documented that antigen presentation by pulmonary dendritic cells (DCs) primes Th2-biased CD4+ T-cell responses. One of the most studied mechanisms of pathogen recognition employed by DCs and other innate cells is through the family of Toll-like receptors (TLRs). Although studies of endogenous, polyclonal CD4+ T-cell responses to A. fumigatus have provided valuable information regarding the general kinetics of CD4+ T-cell activation and have demonstrated the contribution of CD4+ T cells in immunity to this fungal pathogen, they have not provided a full picture of CD4+ T-cell responses to A. fumigatus. Priming of CD4+ T cells by activated DCs presenting their cognate antigen results in vigorous T-cell proliferation and expansion of antigen-specific clones that can mediate protection against infection. Although the role of Th17 CD4+ T-cell responses in infection is just starting to be elucidated, it seems that Th17 CD4+ T-cell responses may be particularly important in immunity to fungi. The studies summarized in this chapter provide extensive experimental data demonstrating the participation of adaptive immune responses, in particular by CD4+ T lymphocytes, in antifungal immunity.
Key Concept Ranking
- Major Histocompatibility Complex Class II
After infection with A. fumigatus conidia, A. fumigatus-specific CD4+ T cells can differentiate along the Th1 or Th2 lineage. CD4+ T cells that differentiate into Th1 cells acquire the capacity to make IFN-γ. Exposure of macrophages and neutrophils to IFN-γ leads to the production of antimicrobial products that promote clearance of A. fumigatus. Th1-mediated enhancement of antifungal responses provides protection from IA. A. fumigatus-specific T cells that differentiate into Th2 are central to the pathogenesis of ABPA. Through the production of IL-4 and IL-13, Th2 T cells promote eosinophil infiltration of the airways and the production of IgE antibodies. This CD4+ Th2-mediated response leads to airway hyperreactivity. Th2 responses also contribute to the progression of IA by limiting Th1 responses.
A. fumigatus conidia and hyphae are recognized by DCs via the TLR family and by the C-type lectin dectin-1. During the process of germination, A. fumigatus exposes β-1,3-glucans as well as unidentified molecules recognized by TLRs. Recognition of β-1,3-glucans by dectin-1 triggers mitogen-activated protein kinases (MAPKs) as well as Syk kinase and CARD9-dependent signals that ultimately lead to NF-κB activation and the production of inflammatory cytokines and chemokines. Both TLR2 and TLR4 mediate recognition of A. fumigatus. Upon engagement, TLR signals are transmitted by adaptor proteins that interact with the receptors via Toll/IL-1 receptor domains (TIR). The adaptor proteins MyD88 and MyD88-adaptor-like (MAL) mediate signals from TLR2 and TLR4. TLR4 signals are delivered by MAL-MyD88 as well as by TRIF-related adaptor molecule (TRAM) and TIR-domain containing adaptor protein inducing IFN-β (TRIF). Together, dectin-1- and TLR-derived signals result in the activation of DCs in response to A. fumigatus infection and influence CD4+ T-cell differentiation.
The potential use of A. fumigatus-specific CD4+ T cells as therapeutics for the treatment of IA has been demonstrated by various approaches. Potential strategies include vaccination and adoptive transfer of antigen-specific T cells. Vaccination of animals via intranasal or subcutaneous delivery of A. fumigatus antigens leads to the development of T-cell responses capable of conferring protection from IA. The systemic delivery of DCs modified to present A. fumigatus antigens can also lead to the induction of protective T-cell responses in treated animals. A. fumigatus-specific CD4+ T cells generated in vivo in infected donor mice can confer protection against IA in recipient animals that have undergone allogeneic bone marrow transplantation. Similarly, human-derived, A. fumigatus-specific CD4+ T cells can be recovered from donors and expanded in vitro with a variety of A. fumigatus antigens. Expanded A. fumigatus-specific T cells have been transferred into bone marrow transplant recipients.