Category: Environmental control of the immune system

Abstract

Huntington disease is a neurodegenerative disorder caused by an expanded polyglutamine (polyQ) repeat within the protein huntingtin (Htt). N-terminal fragments of the mutant Htt (mHtt) proteins containing the polyQ repeat are aggregation-prone and form intracellular inclusion bodies. Improving the clearance of mHtt fragments by intracellular degradation pathways is relevant to obviate toxic mHtt species and subsequent neurodegeneration. Because the proteasomal degradation pathway has been the subject of controversy regarding the processing of expanded polyQ repeats, we examined whether the proteasome can efficiently degrade Htt-exon1 with an expanded polyQ stretch both in neuronal cells and in vitro. Upon targeting mHtt-exon1 to the proteasome, rapid and complete clearance of mHtt-exon1 was observed. Proteasomal degradation of mHtt-exon1 was devoid of polyQ peptides as partial cleavage products by incomplete proteolysis, indicating that mammalian proteasomes are capable of efficiently degrading expanded polyQ sequences without an inhibitory effect on the proteasomal activity.

Keywords: Aggregation, Autophagy, Huntington Disease, Polyglutamine, Proteasome

Authors

Katrin Juenemann, Sabine Schipper-Krom, Anne Wiemhoefer, Alexander Kloss, Alicia Sanz Sanz, and Eric A. J. Reits

Link

https://doi.org/10.1074/jbc.M113.486076

Specialized stromal cells occupy and help define B- and T-cell domains, which are crucial for proper functioning of our immune system. Signaling through lymphotoxin and TNF receptors is crucial for the development of different stromal subsets, which are thought to arise from a common precursor. However, mechanisms that control the selective generation of the different stromal phenotypes are not known. Using in vitro cultures of embryonic mouse stromal cells, we show that retinoic acid-mediated signaling is important for the differentiation of precursors towards the Cxcl13pos follicular dendritic cell (FDC) lineage, and also blocks lymphotoxin-mediated Ccl19pos fibroblastic reticular cell lineage differentiation. Accordingly, at the day of birth we observe the presence of Cxcl13posCcl19neg/low and Cxcl13neg/lowCcl19pos cells within neonatal lymph nodes. Furthermore, ablation of retinoic acid receptor signaling in stromal precursors early after birth reduces Cxcl13 expression, and complete blockade of retinoic acid signaling prevents the formation of FDC networks in lymph nodes.

Authors

Jasper J Koning, Anusha Rajaraman, Rogier M Reijmers, Tanja Konijn, Junliang Pan, Carl F Ware, Eugene C Butcher, Reina E Mebius

Link

https://doi.org/10.1242/dev.199713

Lymph nodes (LNs) aid the interaction between lymphocytes and antigen-presenting cells, resulting in adequate and prolonged adaptive immune responses. LN stromal cells (LNSCs) are crucially involved in steering adaptive immune responses at different levels. Most knowledge on LNSCs has been obtained from mouse studies, and few studies indicate similarities with their human counterparts. Recent advances in single-cell technologies have revealed significant LNSC heterogeneity among different subsets with potential selective functions in immunity. This review provides an overview of current knowledge of LNSCs based on human and murine studies describing the role of these cells in health and disease.

Authors

C Grasso, C Pierie, R E Mebius, L G M van Baarsen

Link

https://doi.org/10.1016/j.it.2021.08.009

Secondary lymphoid organs are critical for efficient interaction between innate antigen presenting cells and adaptive lymphocytes in order to start adaptive immune responses. The efficiency by which these cellular subsets meet is highly increased by the orchestrating role of stromal cells within the secondary lymphoid organs. These cells provide cytokines, chemokines and cell surface receptors necessary for survival and guided migration. This increases the likelihood that antigen specific adaptive immune responses occur. Already from initial formation of secondary lymphoid organs, the interaction of immune cells with stromal cells is crucial and this interaction continues during immune activation. With the recent discovery of many stromal cell subsets new immune micro-niches with specific functions that are orchestrated by stromal cells will be discovered. Here, we will discuss how the development of lymph nodes as well as their specific niches is guided by the interaction of immune cells and stromal cells.

Authors

Jasper J Koning, Reina E Mebius.

Link

https://doi.org/10.1016/j.coi.2020.03.003

Within lymph nodes (LNs), T follicular helper (T_FH) cells help B cells to produce antibodies, which can either be protective or autoreactive. Here, we demonstrate that murine LN stromal cells (LNSCs) suppress the formation of autoreactive T_FH cells in an antigen-specific manner, thereby significantly reducing germinal center B cell responses directed against the same self-antigen. Mechanistically, LNSCs express and present self-antigens in major histocompatibility complex (MHC) class II, leading to the conversion of naive CD4⁺ T cells into T regulatory (T_REG) cells in an interleukin-2 (IL-2)-dependent manner. Upon blockade of T_REG cells, using neutralizing IL-2 antibodies, autoreactive T_FH cells are allowed to develop. We conclude that the continuous presentation of self-antigens by LNSCs is critical to generate antigen-specific T_REG cells, thereby repressing the formation of T_FH cells and germinal center B cell responses. Our findings uncover the ability of LNSCs to suppress the early activation of autoreactive immune cells and maintain peripheral tolerance.

Authors

Reza Nadafi, Catarina Gago de Graça, Eelco D Keuning, Jasper J Koning, Sander de Kivit, Tanja Konijn, Sandrine Henri, Jannie Borst, Rogier M Reijmers, Lisa G M van Baarsen, Reina E Mebius.

Link

https://doi.org/10.1016/j.celrep.2020.03.007

During embryogenesis, lymph nodes form through intimate interaction between lymphoid tissue inducer and lymphoid tissue organizer (LTo) cells. Shortly after birth in mice, specialized stromal cell subsets arise that organize microenvironments within the lymph nodes; however, their direct precursors have not yet been identified. In the bone marrow, mesenchymal stem cells are labeled with GFP in nestin-GFP mice, and we show that during all stages of development, nestin(+) cells are present within lymph nodes of these mice. At day of birth, both mesenchymal CD31(-) and endothelial CD31(+) LTo cells were GFP(+), and only the population of CD31(-) LTo cells contained mesenchymal precursors. These CD31(-)nestin(+) cells are found in the T and B cell zones or in close association with high endothelial venules in adult lymph nodes. Fate mapping of nestin(+) cells unambiguously revealed the contribution of nestin(+) precursor cells to the mesenchymal as well as the endothelial stromal populations within lymph nodes. However, postnatal tamoxifen induced targeting of nestin(+) cells in nes-creER mice showed that most endothelial cells and only a minority of the nonendothelial cells were labeled. Overall our data show that nestin(+) cells contribute to all subsets of the complex stromal populations that can be found in lymph nodes.

Authors

Jasper J Koning, Tanja Konijn, Kim A Lakeman, Tom O’Toole, Keane J G Kenswil, Marc H G P Raaijmakers, Tatyana V Michurina, Grigori Enikolopov, Reina E Mebius.

Link

https://doi.org/10.4049/jimmunol.1501162