The Life Cycle of Dendritic Cells
Leukocytes, erythrocytes, and megakaryocytes are all derived from pluripotent hematopoietic stem cells. In adults, hematopoietic stem cells originate in the bone marrow mainly in the sternum, pelvis, and femur. Hematopoietic stem cells transform into myeloid progenitor cells which are the precursors of granulocyte-macrophage progenitors and megakaryocyte/erythroid progenitors. Granulocyte-macrophage progenitors are colony-forming units and can transform into macrophage-dendritic precursors, neutrophils, eosinophils, and basophils. Macrophage-dendritic precursors then transform into immature dendritic cells. Immature dendritic cells reside in the tissue and have a distinct star-shaped structure.
Dendritic cells are phagocytes that engulf pathogens from their surroundings. They can also be infected with intracellular pathogens and viruses. Depending on the event, dendritic cells can be modified to change their surface proteins that are detected by the cell-surface receptors of natural killer cells. When dendritic cells undergo changes due to infection, changes are detected by the natural killer cells thus, the two cells form a strong connection with a synapse in between. The strong connection of the two cells induces the production of IL-15 which promotes the proliferation, differentiation, and survival of natural killer cells.
The activation of natural killer cells due to its interaction with dendritic cells has important outcomes not only for the lysis of infected cells but it can also improve an ongoing adaptive immune response by the production of IFN-γ which encourages T cell type 1 polarization. Additionally, activated natural killer cells can modify dendritic cells, by killing the more immature dendritic cells as well as activating the dendritic cells to initiate the adaptive immune response. Study suggest that activated, mature dendritic cells have a higher expression of MHC class I molecules which protects them from being killed by natural killer cells. Conversely, immature dendritic cells have lower expression of MHC class I molecules which makes them prone to natural killer cell lysis.
How natural killer cells affect dendritic cells depends on certain conditions. When the number of activated natural killer cells is more than the number of dendritic cells and the innate immunity is succeeding over the infection, the natural killer cells transform into cytotoxic cells killing the dendritic cells which avoid the activation of the adaptive immune response. In contrast, when the number of activated natural killer cells is less than the number of dendritic cells and the innate immunity is failing to fight the infection, the natural killer cells produce cytokines that activate the dendritic cells to differentiate into a type of migratory cell that travels from the infected tissue to the secondary lymphoid tissue. The migration of dendritic cells from the site of infection to the lymphoid tissue is the process that commences the adaptive immune response.
Programmed cell death protein 1 or PD1 is a transmembrane protein expressed by B cells, T cells, and NK cells. This protein interacts with programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2) which are considered co-inhibitory or co-stimulatory molecules. One of the most effective immunotherapies in cancer treatment is the inhibition of programmed death-1 pathways. When PD-L1 binds to PD-1, T cell function is suppressed by inhibiting the CD28 signaling. PD-L1 is expressed in some infiltrating myeloid cells and tumor cells. Myeloid cells are of special interest because they also express B7-1 which is a ligand for PD-L1 and CD28. Researchers have demonstrated that dendritic cells represent an important source of PD-L1. By deleting PD-L1 in dendritic cells, but not in macrophages, tumor growth is suppressed and also enhances anti-tumor responses of CD8+ T cells. Another therapy for cancer is called dendritic cell vaccination which utilizes the main role of dendritic cells in the activation of the innate and adaptive immune responses. It has been shown to induce an immune response by increasing the levels of lymphocytes that infiltrate tumor cells and provide better survivorship to at least some of the patients.
Sources:
Americord. Hematopoietic Stem Cell. https://archive.ph/20140623222517/http://cordadvantage.com/cord-blood-101/hematopoietic-stem-cell
Ferlazzo, G., Morandi, B. (2014). Cross-talks between natural killer cells and distinct subsets of dendritic cells. Front. Immunol. https://www.frontiersin.org/articles/10.3389/fimmu.2014.00159
Oh, S.A., Wu, DC., Cheung, J. et al. PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer. Nat Cancer 1, 681–691 (2020). https://doi.org/10.1038/s43018-020-0075-x
van Willigen, W. W., Bloemendal, M., Gerritsen, W. R., Schreibelt, G., de Vries, I., & Bol, K. F. (2018). Dendritic Cell Cancer Therapy: Vaccinating the Right Patient at the Right Time. Frontiers in immunology, 9, 2265. https://doi.org/10.3389/fimmu.2018.02265
