Dendritic Cells and Their Crucial Role in Modulating Innate Lymphoid Cells for Treating and Preventing Infectious Diseases

Abstract

Two key players in the immune system, dendritic cells (DCs) and innate lymphoid cells (ILCs), interact in a crucial way to fight infectious diseases. DCs play a key role in recognizing pathogens, and ILCs respond to cytokines released by DCs. This response triggers the production of specific effector cytokines that help control pathogens and maintain the body's barrier integrity. DCs have various receptors, including Toll-like receptors (TLRs), that detect microbial components and trigger immune responses. Likewise, ILCs act as essential initial responders in the immune system in viral, bacterial, and parasitic infections. Successfully managing diseases caused by pathogens mainly depends on the combined actions of DCs and ILCs, which work to suppress and eliminate pathogens. DCs also play a crucial role in activating innate and adaptive immune cell subsets, including ILCs. Furthermore, the use of DCs in developing vaccines and immunotherapy for cancers, along with the dedication of many researchers to improve immune responses through DCs, has increased interest in the potential of DC therapies for treating and preventing infectious diseases. This review examines approaches that may enhance DC vaccines and boost anti-infection immune responses by fostering better interactions of DCs with ILCs.

Keywords: dendritic cells; infectious diseases; innate lymphoid cells.

Figure 1

Development and Subsets of Dendritic Cells (DCs). The developmental pathway of DCs from HSCs in the bone marrow is shown. Under the influence of cytokines, such as Flt3l, GM-CSF, and IL-4, as well as key transcription factors, HSCs give rise to various DC subsets, including cDCs, moDCs, and pDCs. These subsets differ in origin and function, but all play crucial roles in antigen presentation, immune activation, and cytokine production [6,7,8,11,15,26].

Figure 2

Different ILC subsets, their main cytokines, and primary roles in infectious disease defense. ILC1s release interferon-gamma (IFN-γ) in response to cytokines such as IL-12, IL-15, and IL-18. IFN-γ activates infected cells, including macrophages (MCs), promoting the production of nitric oxide and reactive oxygen species that are essential for controlling parasites. Both cell types require the transcription factor T-bet for differentiation and are activated in response to intracellular pathogens [1,30]. ILC2s, acting as the innate counterparts to Th2 cells, produce type-2 cytokines, such as IL-4, IL-5, IL-9, IL-13, and amphiregulin, when stimulated by TSLP, IL-25, and IL-33. The differentiation of ILC2s requires the transcription factors GATA3 and RORα, which are activated in response to helminths and environmental agents [30,37]. ILC3s produce IL-22 and IL-17 when stimulated by IL-23 and IL-1β, and they represent the innate equivalents of Th17 cells. The differentiation of ILC3s requires the transcription factor RORγτ, and they become activated in response to extracellular bacteria and fungi [28,37].

Figure 3

Interactions between DC and ILC subsets coordinate pathogen-specific immune responses. The figure illustrates how DCs engage with distinct ILC subsets to coordinate immune responses against specific pathogens. DC-derived cytokines activate different ILC subsets. IL-12 from DCs activates ILC1, inducing the production of IFN-γ and TNF, which contribute to defense against intracellular bacteria such as Listeria monocytogenes [55,60]. During influenza, epithelial damage and DC sensing of viral components both lead to the release of IL-33, which activates lung ILC2s. Upon activation, ILC2s proliferate and secrete IL-4 and amphiregulin. IL-4 suppresses DC responsiveness to type I IFN and reduces their expression of IL-12 and co-stimulatory molecules, impairing their ability to drive Th1 differentiation. Concurrently, ILC2-derived amphiregulin contributes to epithelial repair and mucosal healing, particularly during the resolution phase of infection [34,61]. IL-1β and IL-23 stimulate ILC3 to produce IL-17 and IL-22, enhancing mucosal immunity and supporting Th17 responses against extracellular pathogens, including fungi [62,63]. These interactions underscore the pivotal role of DC–ILC cross-talk in orchestrating pathogen-specific innate immune responses.

Figure 4

Type II immunity (response to helminths and environmental agents). Upon helminth infection, epithelial cells release alarmins that activate ILC2s. Activated ILC2s secrete IL-5 and IL-13. IL-5 recruits eosinophils, which contribute to parasite killing, while IL-13 promotes cDC2 migration to draining lymph nodes by enhancing their response to CCR7 ligands [101]. In the lymph nodes, cDC2s present antigens and express OX40L to support naive CD4⁺ T cell priming and Th2 differentiation. Th2 cells, in turn, produce IL-2, which feeds back to enhance ILC2 proliferation and survival [9,51,103].

Figure 5

Type III immunity against extracellular bacteria and fungi. ILC3s are activated by IL-1β and IL-23 secreted by cDC2s in response to microbial stimuli. Upon activation, ILC3s produce IL-22, which acts on epithelial cells to induce the expression of antimicrobial peptides, such as RegIIIγ and β-defensins, thereby enhancing barrier defense. Additionally, ILC3-derived GM-CSF promotes cDC2 differentiation and supports the maintenance of local DC populations, reinforcing mucosal immunity [37,104].

Figure 6

Strategies to modulate ILCs via dendritic cell-based vaccines. This diagram summarizes four main approaches for modulating ILC responses using DC-based vaccines: (1) subset-specific DC targeting [127], (2) cytokine engineering of DCs [128], (3) use of PRR agonists and adjuvants [129,130], and (4) mucosal delivery [131,132]. Each strategy aims to fine-tune cytokine signaling to activate ILC1, ILC2, or ILC3 subsets, thereby enhancing immunity, mucosal protection, and tissue repair.

Figure 7

Targeting DC subsets to modulate ILC responses. This schematic illustrates how distinct DC subsets, including cDCs, pDCs, and moDCs, can be engineered to present antigens and secrete specific cytokines that selectively activate ILC subsets [15]. For instance, cDCs produce IL-12 to activate ILC1s, pDCs secrete IL-33 to stimulate ILC2s, and moDCs release IL-22 to support ILC3 function. These cytokine-driven interactions enhance mucosal protection and promote tissue repair. In parallel, antigen presentation by DCs also primes T cells, which differentiate into effector subsets that contribute to pathogen clearance [55,113,127,134,137,138,139].