The Role of Dendritic Cells in the Immune System
Dendritic cells (DCs) serve as the master regulators of the immune response by acting as the critical bridge between innate and adaptive immunity, capturing antigens at epithelial barriers, migrating to lymph nodes, and orchestrating T cell responses through antigen presentation and cytokine signaling. 1
Primary Functions of Dendritic Cells
Antigen Capture and Surveillance
DCs position themselves underneath epithelial barriers as professional antigen-presenting cells, waiting to capture foreign entities using their dendrites, which can extend through the epithelial barrier to sense the external environment. 1
DCs utilize specialized surface receptors for antigen uptake, including endocytosis receptors, phagocytosis receptors, and C-type lectin receptors, enabling efficient capture of pathogens and foreign materials. 2
DCs employ various pattern recognition receptors (including Toll-like receptors) to monitor their local environment for danger signals to the body, allowing them to distinguish between harmless antigens and genuine threats. 1, 2
Bridge Between Innate and Adaptive Immunity
Upon activation by danger signals, DCs migrate to lymph nodes where they interact with T cells through antigen-specific signals, co-stimulatory cellular signals, and cytokine release, thereby forming the essential bridge between innate and adaptive immune responses. 1
DCs are responsible for initiating all antigen-specific immune responses and serve as the master regulators by linking the microbial sensing features of the innate immune system to the specificity of the adaptive response. 3
Through their unique T-cell stimulatory capacity, DCs control the initiation of diverse effector functions suitable for eliminating a wide range of pathogens. 4
T Cell Differentiation and Orchestration
DCs orchestrate further immune responses by differentiating various subsets of T cells through the use of antigen-specific signals, additional co-stimulatory cellular signals, and release of specific cytokines. 1
The innate pattern recognition pathways that trigger DC activation are central for skewing adaptive immune responses, tailoring effector functions to match the nature and localization of infection. 4
DCs can induce different T helper cell phenotypes (Th1, Th2, Th17) and regulatory T cells (Tregs) depending on the context of antigen presentation and cytokine milieu. 1
Specialized Functions in Mucosal Immunity
Oral Tolerance Induction
In the gut, CD103+ migratory DCs carry antigens from the intestinal mucosa to mesenteric lymph nodes, where they promote regulatory T cell induction, particularly under the influence of TGF-β and retinoic acid derived from vitamin A. 1
Oral tolerance depends primarily on finely tuned cross-talk between DCs (innate immunity) and T cells (adaptive immunity), as well as on the integrity of the epithelial barrier in the gut. 1
Mucosal DCs play a key role in host defense while maintaining controlled inflammation despite proximity to luminal bacteria, largely regulated by suppressive cytokines TGF-β and IL-10. 1
Bacterial Handling and Antigen Presentation
Nod proteins in DCs control autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry, influencing bacterial handling and antigen presentation. 1
DCs modulate T-cell responses to luminal antigens, serving as key players in regulating tolerance and immunity induced through the intestine. 1
DC Subsets and Functional Specialization
DCs can be broadly classified into conventional DCs (cDC1 and cDC2), plasmacytoid DCs (pDCs), inflammatory DCs, and Langerhans cells, each with unique properties and functions. 5, 2
Different DC subsets harbor intrinsic programs enabling them to react to specific pathogens in a subset-dependent manner, thereby orchestrating appropriate T cell immune responses. 5
DC subsets express unique and conserved molecules based on their ontogeny, surface phenotype, and specialized functions in different tissue microenvironments. 2
Clinical Implications
Immune Regulation Balance
DCs are exceptionally efficient at generating the appropriate type of T cells in response to pathogens while simultaneously guiding the immune system to avoid autoimmune responses to self-antigens, making them paradoxically important in both generating immunity and maintaining tolerance. 3
DCs are capable of inducing efficient immune responses but are also crucial for maintaining peripheral tolerance and inhibiting autoimmune reactions. 5
Immunosuppression in Critical Illness
Professional antigen-presenting cells, including DCs, reduce expression of the MHC class II molecule HLA-DR after the initial inflammatory response in sepsis or critical illness, which is a hallmark of the immunocompromised state. 6
Decreased HLA-DR expression on DCs reflects broader immune dysfunction, including expansion of immunosuppressive cell populations and increased susceptibility to secondary infections. 6
Key Clinical Pitfalls
The window of opportunity for DC-mediated tolerance induction is limited to early developmental periods, particularly during neonatal life when the microbiota is being established. 1
Abnormal functioning of DCs in an immunologically immature environment (such as in cord blood) can lead to immune dysregulation underlying allergic disorders in infancy. 1
DCs must be considered as key players in any therapeutic effort intended to generate vaccines or immunomodulatory therapies, given their central role in controlling immune responses. 3, 7