DCs are the sentinel cells of the immune system, constantly monitoring their external environment. Through their interactions with other immune cell populations, DCs initiate and orchestrate the appropriate immune responses against infectious diseases and cancer, as well as inducing immunological tolerance (Fig.1).
Fig1. DENDRITIC CELLS LINK INNATE AND ADAPTIVE IMMUNITY. DCs sense tissue disturbances and danger signals through their pat tern recognition receptors (PRRs) and undergo phenotypical and functional changes, called “maturation” or “activation.” Upon maturation, DCs upregulate cell surface expression of MHC and co-stimulatory molecules, as well as cytokine production, pro- or anti-inflammatory. Collectively, these changes impact the DC-mediated differentiation, polarization, and immunomodulatory properties of various immune populations, including B and T cells, innate lymphoid cells (ILCs), and natural killer T cells (NKTs). DAMP, Danger-associated molecular pattern; LN, lymph node; PAMP, pathogen-associated molecular pattern.
T Cells
The hallmark function of DCs is to orchestrate T cell responses. By guiding T cell activation and differentiation in response to the inflammatory insults, DCs serve as a central bridge between innate and adaptive immunity. T cell priming by DCs takes place primarily at the LNs, which are specialized immune organs that are linked by lymphatic vessels. LNs are made up of the outer cortex and inner medulla surrounded by a fibrous capsule and mainly contain lymphocytes and B and T cells. T cells reside in the deeper part of the outer cortex, also called the paracortex or T cell zone. This is where T cells and DCs encounter one another. T cells (naïve and central memory) and DCs (primarily mDCs) both express the homing receptor CCR7, which permits trafficking in response to the CCR7 ligands, CCL19, and CCL21, expressed by cells in the LN paracortex. T cell activation is initiated only when T cells encounter a DC presenting their cognate antigen. Increasing the likelihood of a successful encounter, both DCs and T cells are motile and continuously interact with each other in the absence of antigen recognition. DCs are estimated to contact approximately 500 different T cells per hour in the LN. Upon successful encounters, T cell motility decreases, and T cells form stable, long-lasting interactions with DCs. This sustained engagement with DCs stimulates T cells and results in T cell expression of activation markers, effector cytokines, and subsequently clonal expansion. As activated T cells begin proliferating, they regain their motility and exit LNs and return to circulation.
T cell responses can be categorized into three main stages: activation, differentiation, and memory formation. Fully efficient antigen-specific T cell activation requires three distinct signals. Signal 1 is the engagement of the T cell receptor (TCR) with the cognate peptide–MHC complex on APCs. Signal 2 is the co-stimulation and signal 3 is provided by the cytokine milieu. TCRs recognize antigenic peptides only in the context of MHC molecules. TCR binding to pMHC complex is the first trigger for T cell activation and initiates a cascade of downstream signaling, inducing a transcriptional program regulating cellular function. TCR triggering leads to membrane reorganization and formation of the immunological synapse between T cells and APCs. In addition to TCR clusters, co-stimulatory receptors are also recruited to the site. Co-stimulation acts to amplify or counteract the initial activating signals provided by TCR-pMHC interaction. Co-stimulatory molecules are expressed on APC and include the B7.1 (CD80) and B7.2 (CD86), which ligate to CD28 on T cells. Notably, a new member of the B7 family expressed by DCs, B7-DC or programmed death ligand 2 (PD-L2), stimulates naïve T cells highly efficiently. Co-stimulation may also lead to suppression of T cells responses, thereby preventing over-stimulation and autoimmune reactions. For example, binding of B7 ligands to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antagonizes CD28 signaling and inhibits T cell activation. Similarly, engagement of PD-L1 and PD-L2 on DCs with PD-1 on T cells downregulates T cell responses. Importantly, activation of T cells when co-stimulation is absent or suboptimal results in T cell anergy. Co-stimulatory molecules also impact effector T cell differentiation.
Signal 3, provided by cytokines in the microenvironment, deter mines the skewing of the T cell response such that naïve T cells may terminally differentiate toward different subsets with distinct functions and phenotypes. Classically, these phenotypes are grouped as T-helper cell types Th1 and Th2. IL-12 and IL-4, cytokines produced by DCs, are key determinants of initiation or amplification of Th responses. IL-12 and IFN-γ induce a Th1 phenotype, in which T cells produce IFN-γ, TNF-α, IL-2 and eradicate intracellular pathogens. IL-4 induces a Th2 phenotype with T cells producing IL-4, IL-5, and IL-13, which are important for controlling extracellular parasites. The T cell skewing capacity of DCs depends on several variables. For example, DC expression of T-bet is required for the induction of Th1 responses. DCs activated by human thymic stromal lymphopoietin (TSLP) skew T cells to a Th2 phenotype. The duration of DC activation is also critical for T cell skewing. Prolonged activation causes IL-12 depletion and results in “exhausted DCs,” which induce Th2 or nonpolarized T cells. Antigen concentration also determines the direction of T cell skewing, where DCs skew T cells toward Th1 or Th2 phenotypes depending on whether they are presenting high or low amounts of antigen, respectively, which in turn depends on the maturation state of the DCs and consequences of environmental exposure.
The differentiation of naïve T cells into different effector subsets is complex as the inflammatory milieu is comprised of a multitude of cytokines and distinct immune cell subsets. Therefore, a spectrum of T cell phenotypes beyond Th1 and Th2 exists, such as Th9, Th22, Th17, TFH cells, and regulatory T (Treg) cells. DCs can polarize naïve T cells toward these phenotypes as well. For example, iDCs produce IL-6, IL-1β, TGF-β, and IL-23 and efficiently induce TH17 cell polarization. IL-12, together with IL-23 and TGF-β, cytokines produced by activated DCs, induce the differentiation of naïve CD4+ T cells into TFH cells, which secrete IL-21 and regulates B cell responses. Tolerogenic DCs secrete IL-10 and TGF-β and induce the generation of immunosuppressive Tregs.
B Cells
Due to their ability to present antigens and mediate humoral responses, B cells are involved in both innate and adaptive immunity.
DCs are important regulators of B cell responses. DCs influence B-cell proliferation, isotype switching, and plasma cell differentiation. DCs and B cells primarily interact in the outer cortex of LNs, as well as in the germinal centers of LNs or spleen. Unlike T cells, B cells recognize antigens in unprocessed native form. DCs possess specialized non degradative pathways, in which endocytosed antigens are retained intact and recycled to the cell surface without antigen degradation. Therefore, DCs can present internalized antigens in their native state to B cells, engaging the B cell receptor (BCR). Depending on the multivalency of the antigen triggering BCR and the engagement of co-stimulatory molecules, B cells may activate without needing further help. However, if the triggering antigens are of low valency, in order to activate, B cells require help from CD4+ T cells, mainly for the engagement of CD40 by CD40L present on T cells. B cell activation can further be augmented by tumor-necrosis factor (TNF)-family ligands produced by DCs, such as B cell activating factor (BAFF) and APRIL. Once activated, B cells begin to clonally expand and form germinal centers, where B cells undergo isotype switching. DCs may influence this process by mediating CD40-independent isotype switching through BAFF and APRIL. Following these events, B cells differentiate into short-lived plasma cells or memory B cells. IFN-α and IL-6, primarily produced by pDCs, also play a role in inducing plasma cell differentiation. Furthermore, follicular DCs, which are present in germinal centers, participate in the maintenance of B cell memory by providing survival signals.
Innate Lymphoid Cells
Innate lymphoid cells (ILCs) are lymphocytes that lack uniquely rear ranged antigen receptors such as those displayed by T and B cells. ILCs comprise three non-cytotoxic cell subsets, namely ILC1, ILC2, ILC3, and a cytotoxic NK cell subset. Due to their functional similarities, ILCs are considered as innate counterparts of T cells with ILC1s, ILC2s, and ILC3s resembling Th1, Th2, and Th17 cells, respectively, while NK cells resemble cytotoxic CD8+ T cells.97 The interactions between DCs and ILCs are complex and further underscore the role of DCs in linking innate and adaptive immunity.
DCs can promote the differentiation of ILC subsets. IL-12, IL-23, IL-1β, and RA produced by DCs regulate dynamic and reversible differentiation between ILC1 and ILC3 subsets. DCs’ ability to produce RA directly improves ILC3 activity by upregulating RORγt and IL-22 expression. RA also controls tissue localization of ILCs by altering ILCs’ expression of homing receptors, resulting in a migration of ILCs from lymphoid tissues to the gut. ILCs can also regulate DCs. For example, RA production by DCs may be induced by ILC2 derived IL-13 and GM-CSF. ILC2-derived IL-13 also controls the migration of activated lung DCs into draining LNs, inducing Th2 skewing of CD4 T cells. Finally, ILC3s activate DCs through the expression of membrane-bound lymphotoxin, thereby promoting T cell responses, and in return DCs improve ILC functions, suggesting feedback loops between ILCs, T cells, and DCs.
The crosstalk between DCs and NK cells impacts NK cell activation and cytolytic activity, as well as the maturation state of DCs. NK cells and DCs can form an immune synapse, potentially helping directional and confined secretion of cytokines as well as facilitating receptor–ligand interactions on one another. Activated NK cells con tribute to DC maturation through TNF-α and IFN-γ secretion. In turn, activated DCs secrete IL-12, IL-18, IL-15, and IFN-α/β, which enhance the IFN-γ secretion, proliferation, and cytotoxicity of NK cells. In some conditions, NK cells can lyse imDCs through NKp30, although mDCs are protected from cytolysis. This might represent a form of “cellular editing” whereby immature and tolerogenic DCs are cleared by NK cells during an ongoing immune response. The interaction between NK cells and DC is likely to take place early during an ongoing immune response. This allows DC to exploit the ability of NK cells to kill tumor or infected cells and to cross-present this material to T cells, suggesting DCs and NK cells play complementary roles in regulating T cell responses.
Other Elements of the Immune System
DCs have proven to be quite versatile in their ability to interact with various constituents of the immune system. For example, they can activate NKT cells by the presentation of the synthetic ligand α-galactosyl ceramide on CD1, inducing the production of cytokines, such as IFN-γ, and resistance to tumors. CD1-restricted γδ T cells, which respond to microbial antigens from Mycobacterium tuberculosis and other organisms, induce maturation of resting DC, and induce IL-12 production. This pathway and the IFN-γ secretion by activated γδ T cells provide the immune system with a source of activated APCs, which can polarize Th1 responses.
In conclusion, the influence of DCs on other cell types of the immune system is broad and integral for the regulation of immunity. Future studies will further determine the roles of the interplay between DCs and the myriad of other immune cells and inform the design of novel therapies to better remedy immunopathology.
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