Adaptive Immunity: The Pivotal Role of Dendritic Cells

Introduction

This section focuses on Dendritic Cells (DCs), which are specialized phagocytic cells that play a crucial role in initiating and shaping the adaptive immune response. As stated by Ralph M. Steinman, "Dendritic cells are required to explain how this remarkable system [the adaptive immune system] is energised and directed". We will explore:

The general characteristics and functions of dendritic cells.
Their process of antigen uptake, activation, migration, and maturation.
The array of receptors and molecules expressed by DCs.
The interaction of DCs with T-lymphocytes in lymph nodes, including the "three-signal model" of T-cell activation.
The Major Histocompatibility Complex (MHC) and its role in antigen presentation.

Dendritic Cells: Initiators of Adaptive Immunity

Specialized Phagocytic Cells: DCs are professional antigen-presenting cells (APCs) that sample their environment for pathogens and other foreign substances.
Initiate Adaptive Immune Response: They are uniquely potent at activating naïve T-lymphocytes, thereby bridging innate and adaptive immunity.
Key Functions:
- Antigen Uptake and Processing: Immature DCs in peripheral tissues are highly phagocytic, capturing antigens.
- Activation and Migration: Upon encountering PAMPs (via Toll-like Receptors and other PRRs) or inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6), DCs become activated. Activated DCs migrate from peripheral tissues via afferent lymphatic vessels to regional lymph nodes.
- Maturation: During migration and within the lymph node, DCs mature, changing their surface molecule expression and function to become potent T-cell activators.
- Antigen Presentation: Mature DCs present processed antigens (peptides) on their surface via MHC molecules to naïve T-cells in the lymph node.
- T-cell Education: DCs "educate" T-lymphocytes to mount an appropriate immune response (e.g., cytotoxic, helper, regulatory) based on the nature of the antigen and the local cytokine environment. They play a pivotal role in antigen-specific T-cell reactivity.

Dendritic Cell Receptors and Surface Molecules

Dendritic cells express a wide array of surface molecules that enable them to sense their environment, interact with other cells, and activate T-cells:

Pattern Recognition Receptors (PRRs): e.g., Toll-like Receptors (TLRs), for recognizing PAMPs.
Danger Receptors: For recognizing DAMPs.
Cytokine/Chemokine Receptors: To respond to local inflammatory signals and to guide migration (e.g., CCR7).
Adhesion Molecules: For interaction with other cells and migration (e.g., L-selectin, integrins, ICAMs - though specific DC adhesion molecules are implied rather than explicitly listed for DC side in, they are part of the general leukocyte extravasation process).
MHC Class I and MHC Class II Molecules: For presenting processed antigens to T-cells.
Co-stimulatory Molecules: e.g., CD80 (B7.1) and CD86 (B7.2), crucial for T-cell activation.
Solute Transporters: For nutrient uptake and metabolic functions.
Others: Various other receptors and surface proteins involved in their diverse functions.

Dendritic Cell Maturation and Migration

The transition from an antigen-capturing cell to a T-cell activating cell involves significant changes:

Immature Dendritic Cells (in peripheral tissues):
- High phagocytic capacity.
- Low expression of co-stimulatory molecules (e.g., CD80/CD86).
- Low expression of MHC Class II molecules.
- Low secretion of pro-inflammatory cytokines.
- Low expression of CCR7 (a chemokine receptor important for migration to lymph nodes).
- Lower rate of glycolysis.
Mature Dendritic Cells (migrating to/in lymph nodes, after encountering pathogens/cytokines/PAMPs/DAMPs):
- Decreased phagocytic capacity (shift from antigen capture to antigen presentation).
- Increased expression of co-stimulatory molecules (CD80, CD86).
- Increased expression of MHC Class II molecules (and MHC Class I) loaded with processed peptides.
- Increased secretion of pro-inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6, IL-12) that influence T-cell differentiation.
- Increased expression of CCR7.
  - CCR7 binds to chemokines CCL19 and CCL21, which are expressed by afferent lymphatic vessels and stromal cells within the lymph node.
  - This interaction drives DC chemotaxis towards and within the lymph node, increases migratory speed, alters cytoarchitecture, enhances endocytosis, and increases DC survival.
  - CCL19 and CCL21 bind to different amino acids on CCR7, and their interaction can trigger different downstream effects (e.g., CCL19 leading to strong but temporal pERK1/2 signaling, while CCL21 might lead to weak but persistent signals; both can induce chemotaxis, but internalization dynamics may differ, with β-arrestin involvement).
- Increased glycolysis to support metabolic demands of an activated cell.

T-cell Homing to Lymph Nodes: Naïve T-cells also migrate from the blood into lymph nodes, primarily through specialized blood vessels called high endothelial venules (HEVs). This process involves:

Tethering/Rolling: Mediated by L-selectin on T-cells binding to adresins on HEVs.
Activation: Chemokines (like CCL19/CCL21) presented on HEVs bind to CCR7 on T-cells, activating them.
Adhesion: Activated T-cells firmly adhere to HEVs via integrins (e.g., LFA-1) binding to ICAMs on endothelial cells.
Transmigration (Diapedesis): T-cells squeeze between endothelial cells to enter the lymph node parenchyma. Once in the lymph node, T-cells scan DCs for presented antigens. Effector T-cells eventually leave the lymph node via efferent lymphatics.

Antigen Presentation by Dendritic Cells: The Three-Signal Model

For a naïve T-cell to become fully activated, differentiate, and proliferate, it typically requires three signals provided by the mature dendritic cell:

Signal 1: Antigen Recognition (MHC-Peptide : TCR)

This is the antigen-specific signal.
The T-cell receptor (TCR) on the T-cell surface, along with a co-receptor (CD4 or CD8), recognizes a specific peptide antigen presented by an MHC molecule on the DC surface.
- MHC Class I: Presents peptides derived from endogenous proteins (e.g., viral proteins synthesized within an infected cell, or self-proteins from normal cell turnover). These peptides are processed in the proteasome, transported into the ER by TAP (Transporter associated with Antigen Processing), and loaded onto MHC Class I molecules. MHC Class I is expressed on all nucleated cells and presents to CD8+ T-cells (which typically become cytotoxic T-lymphocytes - CTLs).
- MHC Class II: Presents peptides derived from exogenous proteins (e.g., from extracellular bacteria or viruses that have been phagocytosed by the APC). These antigens are processed in endosomes/lysosomes, and peptides are loaded onto MHC Class II molecules. MHC Class II is expressed primarily on professional Antigen Presenting Cells (APCs) like dendritic cells, macrophages, and B-cells. It presents to CD4+ T-cells (which typically become helper T-cells - Th).
Major Histocompatibility Complex (MHC) / Human Leukocyte Antigen (HLA):
- Encoded by a highly polymorphic gene cluster on the short arm of chromosome 6 in humans (>200 genes/pseudogenes). The human MHC is called HLA.
- MHC Class I molecules (e.g., HLA-A, HLA-B, HLA-C) consist of a polymorphic α chain and a non-polymorphic β2-microglobulin. The peptide-binding cleft is formed by the α1 and α2 domains of the α chain.
- MHC Class II molecules (e.g., HLA-DP, HLA-DQ, HLA-DR) consist of polymorphic α and β chains. The peptide-binding cleft is formed by the α1 and β1 domains.
- The high polymorphism (many different alleles for each MHC gene in the population, e.g., HLA-A has 20,182 alleles, HLA-B 7,407 alleles listed in the slide) means that different individuals express different MHC molecules, which can bind and present different sets of peptides. This diversity is crucial for the population's ability to respond to a wide range of pathogens. Each MHC molecule can bind numerous different peptides, and some peptides can bind to several different MHC molecules.
- MHC genes are inherited as haplotypes (sets of alleles on one chromosome) from each parent.

Signal 2: Co-stimulation

This signal confirms that the antigen is associated with danger or infection and is crucial for full T-cell activation; Signal 1 alone can lead to T-cell anergy (unresponsiveness) or deletion.
Provided by the interaction of co-stimulatory molecules on the DC (e.g., CD80 (B7.1) and CD86 (B7.2)) with their receptors on the T-cell (e.g., CD28).
CD28 signaling: Enhances T-cell proliferation, cytokine release, metabolic adaptations, and survival. It activates intracellular signaling pathways involving NF-AT, AP-1, and NF-κB, which regulate T-cell activity.
Other Co-stimulatory/Co-inhibitory Interactions:
- ICOS (Inducible T-cell Co-stimulator) on T-cells binds to ICOSL on DCs; can provide both activating and inhibitory signals depending on context.
- CD40L on activated T-cells binds to CD40 on DCs, providing activation signals back to the DC (licensing it to activate CD8+ T-cells more effectively) and also promoting T-cell help for B-cells.
- CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) on T-cells is an inhibitory receptor that binds CD80/CD86 with higher affinity than CD28, playing a role in downregulating T-cell responses.
- PD-1 (Programmed Death-1) on T-cells is another key inhibitory receptor that binds to PD-L1 or PD-L2 on DCs (and other cells, including tumor cells). PD-1 signaling dampens T-cell activation, effector function, proliferation, and survival, playing a crucial role in maintaining peripheral tolerance and preventing autoimmunity. It is a major target for cancer immunotherapy (checkpoint blockade).
The Immune Synapse: The interface between the T-cell and APC, where these molecular interactions occur, is a highly organized structure called the immunological synapse. It includes clustering of TCR/MHC-peptide, co-stimulatory molecules, and adhesion molecules (e.g., LFA-1 on T-cell binding ICAM-1 on APC; CD2 on T-cell binding CD48/CD58 (not CD59 as on slide) on APC). CD4/CD8 co-receptors and molecules like CD3 (part of TCR complex) and CD45 (tyrosine phosphatase) are also integral.

Signal 3: Cytokines (Differentiation)

Cytokines secreted by the DC (and other cells in the local microenvironment) in response to the PAMPs/DAMPs encountered, direct the differentiation of the activated CD4+ T-cell into different effector subtypes (e.g., TH1, TH2, TH17, TFH (follicular helper), TREG (regulatory T-cells)).
Each subtype has distinct functions and produces a characteristic set of cytokines.
The specific cytokines involved (Signal 3) are determined by the nature of the pathogen or stimulus that activated the DC.
- TH1 differentiation: Often driven by IL-12 and IFN-γ (IFN-γ can be from NK cells or early T-cells). Key transcription factor: T-bet. TH1 cells produce IFN-γ, promoting cell-mediated immunity against intracellular pathogens. STAT4 signaling is involved.
- TH2 differentiation: Often driven by IL-4. Key transcription factor: GATA3. TH2 cells produce IL-4, IL-5, IL-13, promoting humoral immunity, defense against helminths, and allergic responses. STAT6 signaling is involved.
- TH17 differentiation: Driven by cytokines like TGF-β plus IL-6, or IL-21, IL-23. Key transcription factor: RORγt. TH17 cells produce IL-17, IL-21, involved in defense against extracellular bacteria and fungi, and contributing to some autoimmune inflammation. STAT3 signaling is involved.
- TFH (Follicular Helper T-cell) differentiation: Driven by IL-6 and IL-21. Key transcription factor: Bcl-6. TFH cells migrate to B-cell follicles and provide essential help for B-cell activation, antibody production, and germinal center formation. STAT3 signaling is involved.
- TREG (Regulatory T-cell) differentiation (induced TREGs): Driven by TGF-β (and sometimes IL-2 in the absence of strong pro-inflammatory signals). Key transcription factor: FoxP3. TREG cells produce IL-10, TGF-β, and play a crucial role in suppressing immune responses and maintaining self-tolerance.