Abstract 2662: Mitochondrial genetics appear to alter immune cell development/trafficking

Author(s):  
Thomas C. Beadnell ◽  
Amanda E. Brinker ◽  
Cori Fain ◽  
Carolyn J. Vivian ◽  
Danny R. Welch
Author(s):  
T.C. Beadnell ◽  
C. Fain ◽  
C.J. Vivian ◽  
J.C.G. King ◽  
R. Hastings ◽  
...  

Science ◽  
2014 ◽  
Vol 345 (6204) ◽  
pp. 1574-1574
Author(s):  
L. M. Zahn
Keyword(s):  

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Bumsik Cho ◽  
Carrie M. Spratford ◽  
Sunggyu Yoon ◽  
Nuri Cha ◽  
Utpal Banerjee ◽  
...  

2013 ◽  
Vol 43 (2) ◽  
pp. 182-195 ◽  
Author(s):  
Anand S. Devasthanam ◽  
Thomas B. Tomasi

2018 ◽  
Vol 236 (2) ◽  
pp. 99-109 ◽  
Author(s):  
Annica Andersson ◽  
Anna E Törnqvist ◽  
Sofia Moverare-Skrtic ◽  
Angelina I Bernardi ◽  
Helen H Farman ◽  
...  

Apart from the role of sex steroids in reproduction, sex steroids are also important regulators of the immune system. 17β-estradiol (E2) represses T and B cell development, but augments B cell function, possibly explaining the different nature of immune responses in men and women. Both E2 and selective estrogen receptors modulators (SERM) act via estrogen receptors (ER). Activating functions (AF)-1 and 2 of the ER bind to coregulators and thus influence target gene transcription and subsequent cellular response to ER activation. The importance of ERαAF-1 and AF-2 in the immunomodulatory effects of E2/SERM has previously not been reported. Thus, detailed studies of T and B lymphopoiesis were performed in ovariectomized E2-, lasofoxifene- or raloxifene-treated mice lacking either AF-1 or AF-2 domains of ERα, and their wild-type littermate controls. Immune cell phenotypes were analyzed with flow cytometry. All E2 and SERM-mediated inhibitory effects on thymus cellularity and thymic T cell development were clearly dependent on both ERαAFs. Interestingly, divergent roles of ERαAF-1 and ERαAF-2 in E2 and SERM-mediated modulation of bone marrow B lymphopoiesis were found. In contrast to E2, effects of lasofoxifene on early B cells did not require functional ERαAF-2, while ERαAF-1 was indispensable. Raloxifene reduced early B cells partly independent of both ERαAF-1 and ERαAF-2. Results from this study increase the understanding of the impact of ER modulation on the immune system, which can be useful in the clarification of the molecular actions of SERMs and in the development of new SERM.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4294-4294
Author(s):  
Sara A. Rubin ◽  
Chloé S. Baron ◽  
Alexandra F. Corbin ◽  
Song Yang ◽  
Leonard I. Zon

Abstract The advent of single-cell RNA sequencing (scRNA-seq) has greatly expanded our appreciation for cell state diversity beyond classical developmental hierarchies and simple population subsets. In particular, rich transcriptional heterogeneity has been observed within immune cell populations leading to the identification of novel cell types. Except for a few notable exceptions, intensive work in this area has largely been confined to mammals. Much of the transcriptional profiling of blood cell development in zebrafish has failed to capture early stages of lymphocyte development as the majority of research has not included thymus datasets or captured sufficient marrow B cells to explore developmental trajectories. To gain insight into T and B cell development in the zebrafish and immune cell diversity more broadly, we performed scRNA-seq using 10x Genomics Next GEM technology on adult zebrafish kidney marrows (n = 5 biological replicates) in addition to whole juvenile thymi at 4 weeks post-fertilization (wpf) (n = 4 technical replicates) and whole adult thymi at 3-4 months post-fertilization (n = 4 biological replicates). After filtering out low quality cellular barcodes, 34,492 kidney marrow cells and 35,268 thymus cells remained for analysis. With respect to T cell development, we identified putative early thymic progenitors from their clustering with hematopoietic stem and progenitor cells and shared transcriptional signatures, including the enrichment of CD34, CSF1R, FLI1, and DNMT3B human orthologs. Multiple subsets of thymic and marrow T cells were characterized, including a subset of gamma delta T cells readily identified by their expression of T-cell receptor gamma and delta chain components and expression of a SOX13 ortholog in addition to a Th2-like population expressing IL4, IL13, and GATA3 orthologs. Among other immune cell populations, rich transcriptional diversity was present. Two distinct populations of B cells, largely mutually exclusive for ighd and ighz expression (dual detection <1%), were present across all datasets, including the 4 wpf thymi, a surprisingly early time point in zebrafish B cell ontogeny. A clustering of the adult datasets demonstrated ighz predominance in the thymus (63% of thymic B cells), whereas the majority of marrow B cells (85%) fell within the ighd cluster. Stages of B cell development were also clearly evident, with the earliest B cell progenitors expressing orthologs of human PAX5, DNTT, RAG1, and RAG2, in addition to sid1, an understudied gene proposed to be orthologous to VPREB1. The expression of dntt was notably absent from more mature subsets of rag1 and rag2+ B cell progenitors, analogous to its expression in mammals. Transcriptional signatures unique but reminiscent of mammalian dendritic cell subsets were identified: Plasmacytoid-like dendritic cells characterized by high expression of TLR7, TLR9, and IRF8 orthologs and conventional-like dendritic cells characterized by high expression of CKB, BATF3, and ZNF366 were present in both marrow and thymus datasets, suggestive of greater dendritic-like cell diversity in the zebrafish than previously appreciated. These findings illustrate the power of single-cell transcriptional profiling for illuminating immune cell development and heterogeneity in the zebrafish, demonstrating increasing parallels to the mammalian system. Disclosures Zon: Celularity: Consultancy; Branch Biosciences: Current holder of individual stocks in a privately-held company, Other: Founder; Scholar Rock: Current equity holder in publicly-traded company, Other: Founder; Amagma Therapeutics: Current holder of individual stocks in a privately-held company, Other: Founder; CAMP4 Therapeutics: Current holder of individual stocks in a privately-held company, Other: Founder; Fate Therapeutics: Current equity holder in publicly-traded company, Other: Founder; Cellarity: Consultancy.


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