Dendritic cells are specialized immune cells that act as sentinels of the immune system, constantly surveying the body for signs of infection or danger. They bridge the innate immune system, which provides immediate, non-specific defense, and the adaptive immune system, which develops highly specific, long-lasting protection. This connection is central to orchestrating effective immune responses.
The Origin of Dendritic Cells
Dendritic cells originate from hematopoietic stem cells, which are multipotent cells located in the bone marrow. These stem cells are capable of developing into all types of blood cells, including various immune cells. The journey from a hematopoietic stem cell to a mature dendritic cell involves a series of differentiation steps.
Initially, hematopoietic stem cells give rise to more committed progenitor cells, often involving an intermediate stage known as common dendritic cell precursors (CDPs). CDPs are progenitor cells that can differentiate into various dendritic cell subsets.
Dendritic cells can follow two main developmental pathways: the myeloid pathway and the lymphoid pathway. The myeloid pathway gives rise to conventional dendritic cells (cDCs), while the lymphoid pathway is associated with plasmacytoid dendritic cells (pDCs). However, pDCs can also arise from myeloid precursors, indicating some flexibility in their developmental paths.
Factors like cytokines and growth factors significantly influence dendritic cell differentiation. For example, FMS-like tyrosine kinase 3 ligand (FLT3L) is a cytokine known to induce the development of hematopoietic stem and progenitor cells into various dendritic cell subsets, including cDCs and pDCs.
Main Types of Dendritic Cells
Dendritic cells are broadly categorized into several main types, each with distinct locations and roles in the immune system. Conventional dendritic cells (cDCs) are the most common type and are further divided into two major subsets: cDC1 and cDC2. These cells are found in various tissues, including the blood and lymphoid organs, where they perform general immune surveillance.
cDC1s are specialized in presenting antigens on Major Histocompatibility Complex (MHC) Class I molecules, a process known as cross-presentation. This function allows them to activate CD8+ T cells, or cytotoxic T lymphocytes, which directly kill infected or cancerous cells. cDC1s are important in antiviral and anti-tumor immunity.
cDC2s have a diverse range of functions and are primarily involved in presenting antigens on MHC Class II molecules to activate CD4+ T cells, or helper T cells. These helper T cells then orchestrate other immune responses, such as supporting B cell antibody production or enhancing the activity of other immune cells. cDC2s are involved in responses to extracellular pathogens, including bacteria and parasites.
Another distinct type of dendritic cell is the plasmacytoid dendritic cell (pDC). These cells are found in lymphoid organs and peripheral blood, and they are known for producing large amounts of type I interferons, especially during viral infections. Interferons are signaling proteins that play a significant role in antiviral defense.
Langerhans cells are specialized dendritic cells in the epidermis, the outer layer of the skin. They capture antigens that enter through this barrier. While historically classified as dendritic cells, recent research reclassified them as macrophages due to their embryonic origin and macrophage-like properties, though they retain dendritic cell-like functions in immune surveillance.
How Dendritic Cells Activate Immunity
Dendritic cells function as professional antigen-presenting cells (APCs), efficient at initiating adaptive immune responses. The process begins with their ability to capture antigens in peripheral tissues, often sites of infection or injury. Immature dendritic cells continuously sample their environment, internalizing foreign substances through phagocytosis or pinocytosis.
Upon encountering pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) through their pattern recognition receptors, dendritic cells undergo maturation. During maturation, they upregulate molecules necessary for T cell activation and migrate to secondary lymphoid organs, such as lymph nodes, where T cells reside. Mature dendritic cells express chemokine receptor 7 (CCR7), which guides their migration to the T-cell areas of these lymphoid organs.
Once in the lymph nodes, mature dendritic cells present processed antigens to T cells. This presentation involves two main signals for T cell activation. The first signal occurs when the T cell receptor (TCR) on the T cell recognizes a specific antigenic peptide bound within a major histocompatibility complex (MHC) molecule on the dendritic cell surface. CD8+ T cells recognize antigens presented on MHC Class I molecules, while CD4+ T cells recognize antigens presented on MHC Class II molecules.
The second signal, known as co-stimulation, is also required for full T cell activation. This signal is provided by specific co-stimulatory molecules on the dendritic cell surface, such as CD80 and CD86, which bind to receptors like CD28 on the T cell. Without this second signal, T cells may become anergic, meaning they become unresponsive. This two-signal system ensures that T cells are only activated when a genuine threat is present, preventing unwanted immune responses against harmless substances.
Dendritic Cells in Disease and Therapy
Dendritic cells play a significant role in various diseases and are increasingly targeted in therapeutic strategies. Their ability to initiate immune responses makes them central to vaccine development. Vaccines introduce antigens to the body, which dendritic cells capture, process, and present to T cells. This elicits a protective adaptive immune response and generates immunological memory against future infections.
In cancer immunotherapy, dendritic cells are a focal point for novel treatments. Dendritic cell vaccines are a cell therapy where a patient’s own dendritic cells are isolated, loaded with tumor-specific antigens, and re-injected into the patient. The goal is to train the patient’s immune system to recognize and attack cancer cells. While these vaccines have shown promise in inducing anti-tumor responses, their effectiveness can vary.
Checkpoint inhibitors, another class of cancer immunotherapies, indirectly enhance dendritic cell function. These drugs block proteins that normally suppress immune responses, allowing existing anti-tumor T cells to become more active. By reducing immune suppression, checkpoint inhibitors can create a more favorable environment for dendritic cells to prime and activate T cells against tumors.
Dysregulated dendritic cell function can also contribute to autoimmune diseases, where the immune system mistakenly attacks the body’s own tissues. In such conditions, dendritic cells might present self-antigens in an activating manner, leading to the proliferation of self-reactive T cells. Therapeutic approaches in autoimmunity often aim to restore immune tolerance by modulating dendritic cell activity.
Pathogens can also manipulate dendritic cells to evade the immune system. Some viruses and bacteria have evolved mechanisms to interfere with dendritic cell maturation or antigen presentation, allowing them to establish infections. Understanding these interactions is important for developing new strategies to combat infectious diseases.