Pathological and protective roles of dendritic cells in Mycobacterium tuberculosis infection: Interaction between host immune responses and pathogen evasion

Abstract

Dendritic cells (DCs) are principal defense components that play multifactorial roles in translating innate immune responses to adaptive immunity in Mycobacterium tuberculosis (Mtb) infections. The heterogeneous nature of DC subsets follows their altered functions by interacting with other immune cells, Mtb, and its products, enhancing host defense mechanisms or facilitating pathogen evasion. Thus, a better understanding of the immune responses initiated, promoted, and amplified or inhibited by DCs in Mtb infection is an essential step in developing anti-tuberculosis (TB) control measures, such as host-directed adjunctive therapy and anti-TB vaccines. This review summarizes the recent advances in salient DC subsets, including their phenotypic classification, cytokine profiles, functional alterations according to disease stages and environments, and consequent TB outcomes. A comprehensive overview of the role of DCs from various perspectives enables a deeper understanding of TB pathogenesis and could be useful in developing DC-based vaccines and immunotherapies.

Keywords: Mycobacterium tuberculosis; dendritic cells; host-directed strategy; pathogenesis; protective immunity; vaccine.

Figure 1

Bidirectional interactions between DCs and diverse cells are involved in the TB pathogenesis and protective response DCs do not function in the unilateral direction of pathogen uptake-migration-Ag presentation interaction with T cells. Bidirectional interactions between DCs and diverse cells are involved in the TB pathogenesis. (A) DCs secrete IL-12 that induce a Th1 immune response secreting IFN-γ or GM-CSF. Conversely, IFN-γ derived from activated T cells (A) and NK cells (F) can induce DC activation, and differentiation into mature DCs can be promoted. (B) CD8⁺ T cells are activated by DCs to secrete granzyme B or perforin, and CD8⁺ T cells simultaneously induce apoptosis of infected cells such as macrophages, thereby enabling effective Ags uptake by DCs. (C) IgG-produced B cells can bind to specific Ags, resulting in the formation of immune complexes. The function of DCs is affected by whether Abs or immune complexes bind to the inhibitory or activating Fcγ receptors with varying binding affinity depending on their isotype. (D) Apoptosis of macrophages is suppressed by NuoG or SecA in an Mtb-dependent manner, resulting in effective Ag presentation that could be suppressed, thereby suppressing T cell activation. (E) Mtb-infected neutrophils secrete alarmins, CCL3, and CCL5 through degranulation to promote migration of immature DCs to the infection site, DC migration to LNs, and induce maturation. In contrast, Mtb inhibits neutrophil apoptosis in a NuoG-dependent manner, thereby preventing this protective response. (F) In NK cells, DC maturation can be induced through IFN-γ secretion. (G) Alveolar epithelial cell type II secretes β-defensin to induce the migration of immature DCs to the infection site, and simultaneously regulates the DC Hif1α-NOS2 axis to induce DC maturation. (H) DCs expressing integrin β2 bind to endothelial cells and transmigrate to afferent lymphatic vessels. Mtb infection disturbs the expression of CD18 containing integrin β2, decreasing DC migration to local lymph nodes. GM-CSF, granulocyte-macrophage colony-stimulating factor; GzmB, granzyme B; FcγR, Fc Gamma Receptors; ITIM, immunoreceptor tyrosine-based inhibitory motif; ITAM, immunoreceptor tyrosine-based activation motif; dLN, draining lymph node.

Figure 2

Immune alteration mechanisms of Mtb targeting DCs. (A) DC differentiation is affected by Mtb. Mtb-Ags such as Acr-1 or α-glucan, a cell wall component of Mtb, induce altered differentiation of DCs with reduced function. (B) Mtb, its cell walls components and Mtb-Ags are recognized by DCs via TLRs and CLRs, which could induce alteration of DC function by down regulating the expression of costimulatory molecules (CD80, CD83, and CD86) and MHC class II to suppress maturation, and increase the expression of inhibitory molecules such as PD-L1 and IDO. (C) Mtb inhibits Ag presentation. Esx-1 induces phagosomal damage and together with PE-PGRS47, inhibits phagosome-lysosme fusion. Meanwhile, ManLAM suppresses autophagosome formation by inhibiting expression of microtubule-associated light chain 3 (LC3) protein. (D) Reduced expression of CCR7 by Mtb infection affect DC migration to the LNs by lowering response to CCL19 and CCL21. DCs captured in lung tissue promote the formation of larger or multifocal granulomas. (E) DC migration to lymph nodes causes leakage of Mtb-Ags in a kinesin-2 dependent manner, and induces suboptimal T cell proliferation by the inefficient by Mtb-induced maturation. Cytokine profiles such as increased IL-10 and decreased IL-12p70 interfere with protective Th1 type polarization. (F) These processes induce a delayed T cell response to lung tissue infection sites, and suppress TB disease control by forming suboptimal T cell immunity. TLRs, Toll-like receptors; CLRs, C-type lectin receptors; PD-L1, programmed death-ligand 1; IDO, indoleamine 2,3-dioxygenase; LNs, lymph nodes; CCR, chemokine receptor; CCL, chemokine ligand.

Figure 3

DC-based approaches to overcome TB disease. (A) Injection of Flt3L, GM-CSF or immunization with a vaccine that produces Flt3L, GM-CSF could increase the absolute number of DCs. (B) In Mtb infection, various CLRs that modulate the function of DCs could be blocked to promote DC maturation. For example, an aptamer such as ZXL-1 can inhibit the binding of ManLAM and mannose receptor. (C) Molecules such as DC-SIGN and Dec-205, mainly expressed on DCs, can be major targets of DC-targeted vaccines, which can be used to enable effective Ag delivery. (D) Adoptive transfer of DCs maturated with an Mtb-Ags increases the absolute number of DCs for interaction with T cells and can be used as a prime or booster vaccination, or as adjunctive therapy for antibiotic therapy to increase treatment efficiency. (E) Efficiently maturated DCs can interact with T cells through improved migration, which can help to configure optimal T cell immunity. (F) Efficient immunization with DCs can induce tertiary lymphoid structures formation such as iBALT, and can provide effective protection against subsequent infection. LNs, lymph nodes; Flt3L, FMS-like tyrosine kinase 3 ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; CLRs, C-type lectin receptors; DC-SIGN, DC-specific intercellular adhesion molecule-3 grabbing nonintegrin; TLS, tertiary lymphoid structure; iBALT, inducible bronchus–associated lymphoid tissue.