Advances in Dendritic-Cell-Based Vaccines against Respiratory Fungal Infections

Abstract

Ever since the discovery of dendritic cells by Ralph Steinman and Zanvil Cohn in 1973, it is increasingly evident that dendritic cells are integral for adaptive immune responses, and there is an undeniable focus on them for vaccines development. Fungal infections, often thought to be innocuous, are becoming significant threats due to an increased immunocompromised or immune-suppressed population and climate change. Further, the recent COVID-19 pandemic unraveled the wrath of fungal infections and devastating outcomes. Invasive fungal infections cause significant case fatality rates ranging from 20% to 90%. Regrettably, no licensed fungal vaccines exist, and there is an urgent need for preventive and therapeutic purposes. In this review, we discuss the ontogeny, subsets, tissue distribution, and functions of lung dendritic cells. In the latter part, we summarize and discuss the studies on the DC-based vaccines against pulmonary fungal infections. Finally, we highlight some emerging potential avenues that can be incorporated for DC-based vaccines against fungal infections.

Keywords: DC-based vaccine; adaptive immune response; dendritic cells; pulmonary fungal infections.

Figure 1

Pulmonary tissue DC subsets. Mucosal CD103⁺ resident cDC1s are located in the basolateral space of the epithelium and can extend their dendrites between epithelial cells directly into the lumen of the airway. CD11b⁺ resident cDC2 and plasmacytoid DCs (pDCs) are located underneath the basement membrane of the lung or in the lung parenchyma. During inflammatory conditions, an activated population of inflammatory DCs expressing CD11b⁺ and Ly6C⁺ are seen in the lung tissue. The alveolar macrophages (AMs) are present in alveolar space. DC, dendritic cell; cDC, conventional dendritic cell.

Figure 2

Functions of DCs. Immature dendritic cells (DCs) perform antigen uptake and processing in the mucosa of the lungs and present the antigenic peptides in MHC-I or MHC-II complexes to cognate TCRs on naïve T cells (Signal I) in regional lymph nodes. Fungal antigen recognition induces the maturation and activation of DCs, resulting in increased expression of co-stimulatory molecules, CD80 and CD86 (Signal II), which bind to CD28 on naïve T cells to initiate their activation. DCs secrete polarizing cytokines (Signal III) which induce the differentiation of T cells into lineage-specific subsets. Th₁/Tc₁ subset produces IFN-γ which enhances the fungal killing and cytokine release by macrophages. Th₂/Tc₂ subset secretes IL-4, IL-13, and IL-5, which increases the number of eosinophils, and mucus secretion, and promotes IgE class switching. Th₁₇/Tc₁₇ subset produces IL-17A and IL-22, which increases the neutrophil recruitment, fungal clearance, and alveolar epithelial cell functions.