Antigen dynamics of follicular dendritic cells

Stromal-derived follicular dendritic cells (FDCs) are a major depot for antigen that are essential for formation of germinal centers, the site where memory and effector B cells differentiate and high-affinity antibody production takes place. Historically, FDCs have been characterized as ‘accessory’ cells that passively support germinal center (GC) responses. However, our recent observations suggest that FDCs actively shape humoral immunity. In this dissertation, we discuss recent findings concerning the antigen acquisition and retention functions of FDCs, and relevant implications for protective immunity. We found that FDCs acquired complement-coated immune complexes (ICs) from noncognate B cells via complement receptors 1 and 2 (CD35 and CD21, respectively) and rapidly internalized them by an actin-dependent pathway. ICs were retained intact within a nondegradative cycling compartment and were displayed periodically on the cell surface where they were accessible to antigen-specific B cells. Furthermore, we discuss how FDCs are involved in persistence of Human Immunodeficiency Virus (HIV) in people on antiretroviral therapy (ART). Treatment with ART substantially reduces viral load and limits disease progression in subjects with HIV infection. Despite the success of ART, it does not cure HIV and discontinuation of treatment results in viral rebound. Growing evidence implicates lymph nodes (LN) as a major site for continued infection of CD4 T cells, but the cell sources of a persistent reservoir within LN remain unclear. We found that human FDC isolated from subjects on ART retain infectious HIV via binding to complement receptor 2 (CD21) within a cycling compartment and transmit infectious virus to CD4 T cells in vitro. Importantly, treatment of the HIV+ FDC with a soluble complement receptor 2 (sCD21-Ig) purges the FDC of HIV virions and prevents transmission of infectious virus in vitro. These results provide evidence that reservoirs are not restricted to infected cells and provide a method to purge one reservoir not targeted by conventional therapy. Our results suggest that sCD21-Ig could be a potential component of new therapeutic strategies to achieve functional cure or viral eradication in ART-treated HIV-infected humans. Finally, we show S. pneumonia binds only in the medulla of the LN and that a subset of dendritic cells (DC), besides B cells) are required for the transport of S. pneumoniae to FDC, independent of macrophages. A robust humoral immune response and germinal center formation requires transport of antigen to the FDC. A better understanding of this process can contribute to improvement of future vaccine design

KLRG1 and NKp46 discriminate subpopulations of human CD117+CRTH2- ILCs biased toward ILC2 or ILC3

textabstractRecently, human ILCs that express CD117 and CD127 but lack CRTH2 and NKp44 have been shown to contain precursors of ILC1, ILC2, and ILC3. However, these ILCs have not been extensively characterized. We performed an unbiased hierarchical stochastic neighbor embedding (HSNE) analysis of the phenotype of peripheral blood CD117+ ILCs, which revealed the presence of three major subsets: the first expressed NKp46, the second expressed both NKp46 and CD56, and the third expressed KLRG1, but not NKp46 or CD56. Analysis of their cytokine production profiles and transcriptome revealed that NKp46+ ILCs predominantly develop into ILC3s; some of them can differentiate into ILC1/NK-like cells, but they are unable to develop into ILC2s. In contrast, KLRG1+ ILCs predominantly differentiate into ILC2s. Single-cell cultures demonstrate that KLRG1+ ILCs can also differentiate into other ILC subsets depending on the signals they receive. Epigenetic profiling of KLRG1+ ILCs is consistent with the broad differentiation potential of these cells

How the COVID-19 pandemic highlights the necessity of animal research

Recently, a petition was offered to the European Commission calling for an immediate ban on animal testing. Although a Europe-wide moratorium on the use of animals in science is not yet possible, there has been a push by the non-scientific community and politicians for a rapid transition to animal-free innovations. Although there are benefits for both animal welfare and researchers, advances on alternative methods have not progressed enough to be able to replace animal research in the foreseeable future. This trend has led first and foremost to a substantial increase in the administrative burden and hurdles required to make timely advances in research and treatments for human and animal diseases. The current COVID-19 pandemic clearly highlights how much we actually rely on animal research. COVID-19 affects several organs and systems, and the various animal-free alternatives currently available do not come close to this complexity. In this Essay, we therefore argue that the use of animals is essential for the advancement of human and veterinary health.Functional Genomics of Systemic Disorder

How the COVID-19 pandemic highlights the necessity of animal research

Contains fulltext : 225123.pdf (publisher's version ) (Closed access)Recently, a petition was offered to the European Commission calling for an immediate ban on animal testing. Although a Europe-wide moratorium on the use of animals in science is not yet possible, there has been a push by the non-scientific community and politicians for a rapid transition to animal-free innovations. Although there are benefits for both animal welfare and researchers, advances on alternative methods have not progressed enough to be able to replace animal research in the foreseeable future. This trend has led first and foremost to a substantial increase in the administrative burden and hurdles required to make timely advances in research and treatments for human and animal diseases. The current COVID-19 pandemic clearly highlights how much we actually rely on animal research. COVID-19 affects several organs and systems, and the various animal-free alternatives currently available do not come close to this complexity. In this Essay, we therefore argue that the use of animals is essential for the advancement of human and veterinary health