Plasmacytoid Dendritic Cells as Cell-Based Therapeutics: A Novel Immunotherapy to Treat Human Immunodeficiency Virus Infection?

Abstract

Dendritic cells (DCs) play a critical role in mediating innate and adaptive immune responses. Since their discovery in the late 1970's, DCs have been recognized as the most potent antigen-presenting cells (APCs). DCs have a superior capacity for acquiring, processing, and presenting antigens to T cells and they express costimulatory or coinhibitory molecules that determine immune activation or anergy. For these reasons, cell-based therapeutic approaches using DCs have been explored in cancer and infectious diseases but with limited success. In humans, DCs are divided into heterogeneous subsets with distinct characteristics. Two major subsets are CD11c + myeloid (m)DCs and CD11c − plasmacytoid (p)DCs. pDCs are different from mDCs and play an essential role in the innate immune system via the production of type I interferons (IFN). However, pDCs are also able to take-up antigens and effectively cross present them. Given the rarity of pDCs in blood and technical difficulties in obtaining them from human blood samples, the understanding of human pDC biology and their potential in immunotherapeutic approaches (e.g. cell-based vaccines) is limited. However, due to the recent advancements in cell culturing systems that allow for the generation of functional pDCs from CD34 + hematopoietic stem and progenitor cells (HSPC), studying pDCs has become easier. In this mini-review, we hypothesize about the use of pDCs as a cell-based therapy to treat HIV by enhancing anti-HIV-immune responses of the adaptive immune system and enhancing the anti-viral responses of the innate immune system. Additionally, we discuss obstacles to overcome before this approach becomes clinically applicable.

Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome

“…Because plasmacytoid dendritic cells (pDCs) constitute the main source of IFN-α in blood ( 25 , 26 ), we assessed the numbers of pDCs and myeloid DCs (mDCs). Interestingly, analysis of mDC and pDC counts revealed a profound depletion of pDCs in patients with MIS-C (p = 0.01; Figure 2G ), as compared to children with COVID-19, while mDCs reduction was not statistically different ( Figure 2H ).…”

“…This is consistent with the observation of low levels of pDCs in the peripheral blood of MIS-C patients, as compared to COVID-19 children. Although many cell types can produce IFN-α after viral infections, pDCs are the major source of this cytokine ( 25 , 26 ). pDCs express receptors for single-stranded RNA or DNA, such as the Toll-like receptor (TLR)-7 and -9 ( 37 , 38 ), which are essential to sense the viral pathogen and to trigger the innate immune response.…”

Type I Interferon Production of Plasmacytoid Dendritic Cells under Control

“…Furthermore, a vaccination of pDCs and/or myeloid DCs loaded with peptide antigens evoked functional antigen-specific T cell responses in patients with chemo-naive castration-resistant prostate cancer, thus it might be a promising immunotherapy approach to treat prostate cancer [243]. Currently, there are ongoing clinical trials using pDC-based vaccines for the treatment of metastatic endometrial cancer and non-small-cell lung cancer as well [244].…”

Modeling Dendritic Cell Pulsed Immunotherapy for Mice with Melanoma—Protocols for Success and Recurrence

“…A modification was performed of this equation to analyze multiple injections. For this model, it was considered that CTLs are activated and replicated by DCs injections whereas the death of CTLs occurs by a death rate given in (3). The model takes into account the number of inactivated cells as constant in the initial conditions.…”

“…The understanding of human Dendritic biology and its potential in immunotherapeutic approaches (e.g., cell-based vaccines) is nowadays limited. However, due to the recent advancements in cell culture systems that allow for the generation of functional DCs from CD34+ hematopoietic stem and progenitor cells (HSPC), studying DCs has become easier [3], in addition to many other related studies see for instance [4]. Besides, recent advances in single-cell sequencing have begun to streamline this process.…”