The Multifaceted Role of T-Helper Responses in Host Defense against Aspergillus fumigatus

Abstract

The ubiquitous opportunistic fungal pathogen Aspergillus fumigatus rarely causes infections in immunocompetent individuals. A healthy functional innate immune system plays a crucial role in preventing Aspergillus-infection. This pivotal role for the innate immune system makes it a main research focus in studying the pathogenesis of aspergillosis. Although sometimes overshadowed by the innate immune response, the adaptive immune response, and in particular T-helper responses, also represents a key player in host defense against Aspergillus. Virtually all T-helper subsets have been described to play a role during aspergillosis, with the Th1 response being crucial for fungal clearance. However; morbidity and mortality of aspergillosis can also be partly attributed to detrimental immune responses resulting from adaptive immune activation. Th2 responses benefit fungal persistence; and are the foundation of allergic forms of aspergillosis. The Th17 response has two sides; although crucial for granulocyte recruitment, it can be involved in detrimental immunopathology. Regulatory T-cells, the endogenous regulators of inflammatory responses, play a key role in controlling detrimental inflammatory responses during aspergillosis. The current knowledge of the adaptive immune response against A. fumigatus is summarized in this review. A better understanding on how T-helper responses facilitate clearance of Aspergillus-infection and control inflammation can be the fundamental basis for understanding the pathogenesis of aspergillosis and for the development of novel host-directed therapies.

Keywords: T-helper cells; adaptive immune response; aspergillosis; immunopathology.

Figure 1

T-helper responses to A. fumigatus. The epithelial cell (EC), dendritic cell (DC) and alveolar macrophage (AM) constitute the innate immune response against A. fumigatus. Engagement of surface pattern recognition receptors (PRRs) on these cells triggers downstream signaling pathway, leading to production of distinct lineage-polarizing cytokines. This, in combination with antigen presentation by via MHC-II and binding of co-stimulatory molecules, in turn lead to activation and differentiation of naïve CD4⁺ T-helper cells to distinct effector lineages: Th1, Th17, Th22, Th2, Th9, Treg and Tr1. These effector cells differentially contribute to either protection against fungal infection, detrimental immunopathology, or in the regulation of the adaptive immune response. EC = Epithelial cell; DC = Dendritic cells; AM = Alveolar macrophages; Th = T-helper cells; IL = Interleukin; IFN = Interferon; TGF = Transforming growth factor; TNF = Tumor necrosis factor; AMP= antimicrobial peptide; CTLA-4 = cytotoxic T-lymphocyte antigen 4; STAT = Signal Transducer and Activator of Transcription, RORγt = RAR-related orphan receptor gamma t; AHR = aryl hydrocarbon receptor; t-Bet = T-box transcription factor 21; GATA3 = Transcription factor GATA-3; PU.1 = Transcription factor PU.1; FOXP3 = Forkhead box P3.

Figure 2

Immune pathways in SAFS and ABPA. Antigen presentation by DCs activates naïve CD4+ T-cells into distinct Th-cell lineages. A predominant non-protective Th2 response is a hallmark in allergic forms of aspergillosis, such as SAFS and ABPA. A distinct characteristic is that the high Th2 response creates an imbalance resulting in low protective Th1 responses. Th2 cells release different cytokines, among them IL-4 and IL-13, which trigger antibody class switching to IgE, a distinct hallmark of SAFS. In addition, these cytokines mediate increased mucus production by respiratory goblet cells, and IL-5, which triggers the recruitment of eosinophils. Abundant mucus production in the airway allows biofilm formation, thus facilitating fungal growth. Furthermore, the absence of fungal clearance leads to continuous airway sensitization with fungal components, activating mast cells and the Th2 axis. Mast cell degranulation releases abundant inflammatory mediators such as histamine and leukotriene, which also contribute to the inflammatory phenotypes of patients. Activation of Th17 cells facilitates recruitment of neutrophils, partly contributing to the persistent immunopathology of these diseases. During ABPA the pulmonary epithelial barrier can become compromised, allowing A. fumigatus to germinate and invade the tissues. SAFS = Severe asthma with fungal sensitization; ABPA = Allergic bronchopulmonary aspergillosis; CF = Cystic fibrosis.

Figure 3

The role of regulatory T-cells in aspergillosis. Regulatory T-cells (Treg) orchestrate the balance of the Th1, Th2 and Th17 response; and this fine-tuning is necessary for effective fungal clearance in the host. In healthy individuals, the protective Th1 response effectively aids the clearance of A. fumigatus, whereas potential damaging excessive Th17 activation is dampened by Treg. A predominant Th2 response in allergic forms of aspergillosis such as SAFS and ABPA, leads to persistent inflammation and fungal colonization. In immunocompromised individuals, failure of innate immune cells to eliminate fungi may cause invasive aspergillosis (IA). When the Th17 response is too potently induced this might lead to excessive neutrophil influx and collateral damage. Fine-tuning of the strong pro-inflammatory responses during aspergillosis is facilitated by Treg, which in turn suppress the Th17/Th2 activity and prevent damage to the host.