Divyan Bavan
Introduction
The adaptive immune system plays an essential role in defending the body from pathogens. This protective role is the consequence of highly coordinated responses to pathogen associated molecular patterns (PAMPs): molecules characteristic of viruses, bacteria, and others. For the effector cells to respond to these PAMPs, they must first be displayed on antigen-presenting cells (APCs). APCs work by displaying antigens—short peptides—on MHC I and MHC II proteins on the cell surface. After migration to lymph nodes, these antigens are presented to T cells. This results in initiation of the adaptive immune response. All these tasks are performed by a specific type of antigen presenting cell: the dendritic cell (DC). The pathways which these cells use are highly relevant for fighting many types of illnesses, including cancer. Therefore, understanding these cells is crucial for developing better therapies to target pathogens.
Antigen Capture and Signalling
Before they are primed by antigens, dendritic cells are found throughout the body in an immature state. Immature DCs express several receptors which enable the recognition of pathogens. Since these receptors recognize patterns associated with pathogens, they are called pattern recognition receptors (PRRs). One example is the C-type lectin class of receptors. These proteins—such as macrophage-mannose receptor (MMR)—bind to specific carbohydrates that are found on the membranes of bacteria and fungi, enabling recognition. The result of binding to these receptors is endocytosis of the pathogen, enabling downstream steps important for antigen presentation. Another type of receptor is the Fc receptor (FcR). This class of receptors binds to the Fc region of antibodies, detecting their neutralization or opsonization of viruses or bacteria, respectively. Binding of these antibodies to the Fc receptors—such as FcγRΙΙ—enables receptor-mediated endocytosis (Guermonperez et al., 2002).
To undergo maturation into mature dendritic cells, signalling receptors are also important. These receptors initiate signalling pathways within the dendritic cell that initiates the upregulation of specific genes. The upregulated genes are important for T cell stimulation, antigen presentation, and dendritic cell migration. Thus, antigen recognition by these receptors is also critical. An example of a signalling receptor is a toll-like receptor (TLR). This receptor is responsible, like the previously mentioned one, for detecting components of pathogens. For example, TLR4 can detect gram-negative bacteria by binding to lipopolysaccharide (LPS). TLR5 can detect more bacteria through binding to the flagellin protein. Having multiple types of TLRs enables high rates of pathogen detection. The result of the signalling pathways is the activation of NF-κB. This transcription factor has many effects on gene expression in dendritic cells: upregulation of MHC transcription, production of cytokines, and increased production of costimulatory receptors. Thus, recognition by these receptors is critical for an effective immune response (Guermonperez et al., 2002).
Migration of Dendritic Cells
To present antigens efficiently, DCs must migrate to the location of naïve T cells. In the body, these locations are draining lymph nodes. It is here where these T cells are circulating. Thus, migration of DCs to these areas is critical for an effective immune response.
As mentioned previously, detection of pathogens by receptors such as TLRs leads to changes in gene expression. One receptor that is upregulated in this process is CCR7. This protein is a chemokine receptor, binding to the ligands CCL19 and CCL21. These chemokines, more specifically CCL21, are produced by lymphatic endothelial cells. When CCL21 binds to CCR7, it induces activation of PI3K. This is because CCR7 is a GPCR that activates this pathway. From here, several proteins are activated which lead to remodelling of the actin cytoskeleton. This is important as the result of this is DC migration (Liu et al., 2021).
Migration is dependent on the formation of a leading edge. This part of the cell moves towards the chemokine, whereas the tail of the cell retracts, allowing movement. This creates a feedback cycle, as migration towards the source of the chemokine leads to a greater stimulus. This results in further movement. The mechanism for this process is dependent on Cdc42, a small GTPase. This protein is controlled by factors such as Dock8. This process repeats until the dendritic cell reaches the draining lymph node. Here, the dendritic cell can present its antigens to the T cell, initiating the adaptive immune response (Liu et al., 2021).
Production of MHC Class I and Class II Proteins
Once the pathogen has been engulfed by the dendritic cell, its proteins can escape into the cytosol. They are quickly ubiquitinated and degraded by the proteosome, along with intrinsic DC proteins. In immature DCs this process is slower and inefficient. However, upon maturation from the signalling receptors, DCs upregulate production of LMP2, LMP7, and MECL-1. These molecules are alternative catalytic subunits to the normal proteosome. When they are present with the other components, an immunoproteasome is formed. This version of the complex prefers to cleave polypeptides after hydrophobic and basic residues, while it is less likely to cleave after an acidic residue. This results in peptides that are better substrates for anchoring to MHC class I molecules (Guermonperez et al., 2002; Murphy et al., 2022).
MHC I proteins are processed within the endoplasmic reticulum (ER). Thus, the peptides must be transported here. This is the role of TAP1 and TAP2. These proteins are localized to the ER membrane and are critical for the presentation of antigens on MHC class I molecules. In fact, defects in the genes encoding TAP1 and TAP2 lead to immunodeficiencies as MHC class I molecules are unable to present antigens properly. MHC class I presentation is ubiquitous among most cells, as it is usually reserved for intracellular proteins, with some exceptions (see Figure 1). The MHC class II pathway, however, is specific to APCs such as dendritic cells (Murphy et al., 2022).
In the MHC II pathway, pathogenic components are degraded within the vesicle itself. This is achieved by acidification of the environment by lysosomes, activating various proteases: cathepsins, asparaginyl endopeptidases, and others. These proteases degrade pathogenic proteins. However, the proteases are also important for processing the MHC II molecule. This protein is first produced as three α/β dimers and a trimeric invariant (Ii) chain. These Ii chains are also associated with a class II-associated invariant chain peptide (CLIP). The Ii chain and CLIP prevent premature peptide binding and misfolding. Once it is synthesized by the ER, the MHC II molecule is carried in a vesicle which fuses to the pathogen-carrying vesicle. The proteases—specifically cathepsin S—cleave the Ii chain, leaving the CLIP behind. Then, HLA-DM binds to the MHC class II, enabling the CLIP to dissociate from the complex and other peptides to bind to it. This results in the production of a complete MHC class II molecule, which is subsequently displayed on the APC’s membrane (Murphy et al., 2022).
Antigen Presentation and Initiation of the Adaptive Immune Response
There are two ways dendritic cells can present antigens to T cells: MHC class I or MHC class II. The former is implicated in activation of CD8+ (cytotoxic) T cells, whereas the latter in CD4+ (helper) T cells. Both pathways are critical for activating the adaptive immune response, with the latter being unique to DCs and other APCs (Murphy et al., 2022).
In the case of MHC class I, CD8 on the cytotoxic T cell makes a contact with the MHC. This enables recognition by the T cell receptor (TCR). If the TCR recognizes the antigen, the T cell is actiated. Similarly, the CD4 protein on helper T cells is required for contact with MHC class II proteins. Activation of the TCR again leads to activation of the T cell. To promote further activation, dendritic cells also express costimulatory molecules. The production of these proteins is upregulated after pathogen detection and promote T cell activation. For example, the receptor CD28 is expressed on naïve T cells prior to activation. This receptor binds to CD80 and CD86, ligands that are expressed on dendritic cells after maturation. Binding of these ligands to CD28 leads to phosphorylation of the receptor’s cytoplasmic domain, fostering several downstream effects. An example of this is the activation of PLC-γ, which is important for transcription factor activation. Thus, costimulatory molecules are necessary for shaping the adaptive immune response (Murphy et al., 2022).
Once T cells are activated, they can release cytokines, increase proliferation of effector cells, and promote cell survival. These effects are necessary for mounting an immune response. Proliferation and the promotion of cell survival lead to more pathogens being discovered and eliminated. The production of cytokines activates other immune cells and further increases the adaptive immune response. Thus, dendritic cells are key to initiating the adaptive immune response (Murphy et al., 2022).
Conclusion
It is evident that dendritic cells play a key role in mounting the adaptive immune response. These cells are able to detect pathogens through PRRs, enabling two outcomes: endocytosis and pro-maturation signalling. The former leads to the engulfment of the pathogen, while the latter leads to expression of important genes for the immune response. Once the pathogen is engulfed, it is destroyed within the acidic vesicle. Proteins from the pathogen are degraded and placed on MHC class II molecules for presentation on the cell surface. Proteins can also escape and reach the cytosol, where they are degraded and placed on MHC class I molecules. Simultaneously, the upregulation of CCR7 leads to the migration of the dendritic cell to a draining lymph vessel. Here, it is surrounded by T cells and present the antigens to them. When the TCR can bind to the MHC-antigen complex, it activates the T cell. This is supported by costimulatory molecules such as CD80 and CD86, which bind to CD28 on the T cell. The result of this is the release of cytokines, proliferation, and cell survival. All these responses are necessary for the adaptive immune response, illustrating the key role dendritic cells play in this process.
*Works Cited*
Guermonprez, Pierre, et al. “Antigen Presentation and T Cell Stimulation by Dendritic Cells.” Annual Review of Immunology, vol. 20, no. 1, Apr. 2002, pp. 621–667, https://doi.org/10.1146/annurev.immunol.20.100301.064828.
Liu, Juan, et al. “Dendritic Cell Migration in Inflammation and Immunity.” Cellular & Molecular Immunology, vol. 18, no. 11, 1 Nov. 2021, pp. 2461–2471, www.nature.com/articles/s41423-021-00726-4, https://doi.org/10.1038/s41423-021-00726-4. Accessed 7 Mar. 2026.
Murphy, Kenneth M, et al. Janeway’s Immunobiology. W. W. Norton and Company, 2022.