Dendritic Cells Of The Skin Are Derived From

Dendritic cells (DCs) in the skin are a crucial component of the cutaneous immune system, playing a pivotal role in immune surveillance and the initiation of immune responses against pathogens and other threats. Understanding their origin and development is key to comprehending their function and how they contribute to overall skin health and immunity.

The Multifaceted Origin of Skin Dendritic Cells

Skin DCs are not a homogenous population but rather a diverse group of cells with varying origins, phenotypes, and functions. This heterogeneity reflects the complex immunological landscape of the skin and the need for specialized immune cells to address different challenges. Skin DCs are primarily derived from hematopoietic stem cells (HSCs) in the bone marrow, which give rise to various DC subsets that populate the skin. These subsets include:

• Langerhans cells (LCs): Located in the epidermis
• Dermal dendritic cells (dDCs): Residing in the dermis

While both LCs and dDCs are crucial for skin immunity, they differ significantly in their origin, development, and function. Let's delve deeper into the origins of these vital immune cells.

Langerhans Cells: Epidermal Sentinels

Langerhans cells (LCs) are a unique subset of DCs found in the epidermis, forming a dense network of immune sentinels. They are characterized by the presence of Birbeck granules, specialized organelles involved in antigen processing and presentation.

Origin and Development

The origin of LCs has been a subject of debate for many years. Initially, it was believed that LCs, like other DCs, were continuously replenished from bone marrow-derived precursors. However, research has revealed a more complex picture:

1. Embryonic Origin: LCs are primarily derived from fetal liver monocytes during embryonic development. These monocytes migrate to the skin and differentiate into pre-LCs, which then mature into fully functional LCs. This initial population of LCs establishes a self-renewing network in the epidermis.
2. Postnatal Maintenance: After birth, the LC population is maintained primarily through self-renewal rather than continuous recruitment from the bone marrow. LCs possess the remarkable ability to proliferate within the epidermis, ensuring a stable and long-lasting immune surveillance system.
3. Bone Marrow Contribution: While self-renewal is the primary mechanism for LC maintenance, bone marrow-derived precursors can contribute to the LC pool under certain conditions, such as inflammation or depletion of the resident LC population. These bone marrow-derived precursors differentiate into LCs and help restore the epidermal immune barrier.

Factors Influencing LC Development

Several factors play a crucial role in the development and maintenance of LCs:

• TGF-β1: Transforming growth factor-beta 1 (TGF-β1) is essential for LC development and differentiation. It promotes the expression of Langerin (CD207), a C-type lectin receptor that mediates the formation of Birbeck granules and is a defining marker of LCs.
• RANKL: Receptor activator of nuclear factor kappa-B ligand (RANKL) is another important factor involved in LC development. It promotes the survival and proliferation of LC precursors in the skin.
• E-cadherin: This adhesion molecule, expressed by keratinocytes, interacts with LCs and helps maintain their localization within the epidermis.

Dermal Dendritic Cells: Dermal Guardians

Dermal dendritic cells (dDCs) are a heterogeneous population of DCs residing in the dermis, the deeper layer of the skin. Unlike LCs, dDCs are not characterized by Birbeck granules and exhibit a more diverse range of phenotypes and functions.

Origin and Development

Dermal DCs are primarily derived from bone marrow precursors that migrate to the skin via the bloodstream. These precursors differentiate into various dDC subsets, each with specialized roles in immune responses. The main subsets of dDCs include:

1. CD1a+ dDCs: These dDCs are similar to LCs in that they can present lipid antigens to T cells. They are also efficient at capturing and processing antigens.
2. CD14+ dDCs: These dDCs express the CD14 marker, which is also found on macrophages. They are involved in the production of cytokines and the activation of T cells.
3. CD103+ dDCs: These dDCs are specialized in capturing antigens from the epidermis and migrating to the draining lymph nodes to initiate T cell responses. They express the integrin αEβ7 (CD103), which allows them to interact with E-cadherin on keratinocytes.
4. Langerhans cell-like dDCs: Under inflammatory conditions, some dDCs can acquire characteristics similar to LCs, including the expression of Langerin. These cells are thought to play a role in the resolution of inflammation and the induction of tolerance.

Factors Influencing dDC Development

The development and differentiation of dDCs are influenced by various factors, including:

• Cytokines: Cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) promote the differentiation of bone marrow precursors into dDCs.
• Chemokines: Chemokines such as CCL2 and CCL20 attract DC precursors to the skin and regulate their migration within the dermis.
• Microenvironment: The local microenvironment in the dermis, including interactions with keratinocytes, fibroblasts, and other immune cells, influences the development and function of dDCs.

The Functional Significance of Skin DC Subsets

The distinct origins and developmental pathways of LCs and dDCs reflect their specialized roles in skin immunity.

Langerhans Cells: Antigen Capture and T Cell Activation

LCs are strategically located in the epidermis to capture antigens that penetrate the skin barrier. They are equipped with various receptors, including Langerin and Fc receptors, that enable them to bind and internalize a wide range of antigens, including pathogens, allergens, and haptens. Once LCs capture antigens, they process them into peptides that can be presented to T cells. LCs then migrate to the draining lymph nodes, where they present these antigens to T cells, initiating an adaptive immune response.

Dermal Dendritic Cells: Diverse Immune Functions

Dermal DCs, with their diverse subsets, perform a wider range of immune functions in the skin. Some dDCs specialize in capturing antigens from the epidermis and transporting them to the lymph nodes, while others are involved in the production of cytokines that regulate inflammation and immune responses. Dermal DCs also play a role in the induction of tolerance, preventing the development of autoimmune reactions against self-antigens in the skin.

• CD103+ dDCs are particularly important for cross-presentation, a process by which DCs present exogenous antigens on MHC class I molecules, activating cytotoxic T lymphocytes (CTLs) that can kill infected or cancerous cells.
• CD14+ dDCs contribute to the inflammatory response by producing cytokines such as TNF-α and IL-1β.
• CD1a+ dDCs can present lipid antigens to T cells, playing a role in the immune response to mycobacteria and other lipid-containing pathogens.

Implications for Skin Diseases

Understanding the origin and function of skin DCs is crucial for developing effective therapies for skin diseases. Dysregulation of DC function can contribute to the pathogenesis of various skin conditions, including:

• Atopic dermatitis: In atopic dermatitis, LCs and dDCs can become activated by allergens, leading to the release of inflammatory mediators and the recruitment of immune cells to the skin.
• Psoriasis: In psoriasis, DCs play a role in the activation of T cells that produce cytokines such as TNF-α and IL-17, which drive the inflammation and hyperproliferation of keratinocytes characteristic of the disease.
• Skin cancer: DCs play a complex role in skin cancer. On the one hand, they can initiate anti-tumor immune responses by activating CTLs that kill cancer cells. On the other hand, they can also promote tumor growth by suppressing anti-tumor immunity or by producing factors that stimulate angiogenesis and metastasis.

Targeting DCs in the skin holds promise for treating these diseases. Strategies under investigation include:

• DC-targeted vaccines: These vaccines aim to deliver antigens specifically to DCs in the skin, enhancing their ability to initiate potent and long-lasting immune responses against pathogens or cancer cells.
• DC-modulating therapies: These therapies aim to modulate the function of DCs in the skin, either by suppressing their activation in inflammatory diseases or by enhancing their ability to stimulate anti-tumor immunity in cancer.

The Impact of Inflammation on Skin DC Origins and Function

Inflammation profoundly influences the origin and function of skin DCs. During inflammatory conditions, the recruitment of bone marrow-derived precursors to the skin is enhanced, leading to an influx of new DCs that can contribute to the immune response.

Changes in DC Populations

Inflammation can alter the balance between different DC subsets in the skin. For example, in chronic inflammatory conditions such as psoriasis, the number of CD14+ dDCs increases, while the number of CD103+ dDCs may decrease. This shift in DC populations can contribute to the pathogenesis of the disease.

Modulation of DC Function

Inflammation can also modulate the function of DCs, altering their ability to capture, process, and present antigens, as well as their capacity to produce cytokines. For example, inflammatory cytokines such as TNF-α and IL-1β can enhance the ability of DCs to activate T cells, but they can also impair their ability to induce tolerance.

Therapeutic Implications

Understanding how inflammation affects the origin and function of skin DCs is critical for developing effective therapies for inflammatory skin diseases. Targeting inflammatory cytokines or modulating DC function may help to restore immune homeostasis in the skin and alleviate the symptoms of these diseases.

Future Directions in Skin DC Research

Research on skin DCs is a rapidly evolving field. Future studies will likely focus on:

• Identifying novel DC subsets: The skin DC network is more complex than previously appreciated. Identifying new DC subsets with specialized functions will provide a more complete understanding of skin immunity.
• Elucidating the mechanisms regulating DC development and differentiation: A deeper understanding of the factors that control DC development and differentiation will allow for the development of more targeted therapies for skin diseases.
• Developing DC-targeted therapies: DC-targeted therapies hold great promise for treating a wide range of skin diseases. Further research is needed to optimize these therapies and to identify the patients who are most likely to benefit from them.
• Investigating the role of DCs in skin aging: As we age, the function of skin DCs declines, contributing to increased susceptibility to infections and skin cancer. Understanding the mechanisms underlying this decline will allow for the development of strategies to rejuvenate the skin immune system and promote healthy aging.

Conclusion

Dendritic cells in the skin are a complex and dynamic network of immune cells that play a crucial role in maintaining skin health and immunity. LCs, originating primarily from fetal liver monocytes and maintained by self-renewal, act as sentinels in the epidermis, capturing antigens and initiating T cell responses. Dermal DCs, derived from bone marrow precursors, perform a wider range of immune functions in the dermis. Understanding the origin, development, and function of these DC subsets is essential for developing effective therapies for skin diseases. Future research will undoubtedly continue to unravel the complexities of skin DC biology and pave the way for new and improved treatments for skin disorders. The intricate dance of these immune cells, influenced by factors like TGF-β1, RANKL, cytokines, and the local microenvironment, highlights the sophistication of the skin's immune system and its vital role in protecting us from the outside world.