The OX40/OX40L Axis Regulates T Follicular Helper Cell Differentiation: Implications for Autoimmune Diseases

Fu, NanNan; Xie, Fang; Sun, Zhi‐Jun; Wang, Qin

doi:10.3389/fimmu.2021.670637

Cited by 42 publications

(28 citation statements)

References 125 publications

(152 reference statements)

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“…In contrast, the second terminally differentiated CD4 Tfh GC cluster was characterized by the expression of TNFRSF4 (OX40; GC Tfh-OX40; Figures 2A and 2B). This population interacts via OX40-OX40L with B cells in the GC, where engagement of OX40L on activated B cells was reported to enhance immunoglobulin (Ig) secretion by PC for an improved maturation process (Fu et al, 2021). Finally, we observed a cluster of Tfh memory cells, a controversial subtype of follicular T cells (Figures 2A-2C) (Crotty, 2014).…”

Section: Resultsmentioning

confidence: 99%

An Atlas of Cells in the Human Tonsil

Massoni-Badosa

Soler-Vila

Aguilar-Fernández

et al. 2022

Preprint

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Palatine tonsils are secondary lymphoid organs representing the first line of immunological defense against inhaled or ingested pathogens. Here, we present a comprehensive census of cell types forming the human tonsil by applying single-cell transcriptome, epigenome, proteome and adaptive immune repertoire sequencing as well as spatial transcriptomics, resulting in an atlas of >357,000 cells. We provide a glossary of 121 annotated cell types and states, and disentangle gene regulatory mechanisms that drive cells through specialized lineage trajectories. Exemplarily, we stratify multiple tonsil-resident myeloid slancyte subtypes, establish a distant BCL6 superenhancer as locally active in both follicle-associated T and B cells, and describe SIX5 as a potentially novel transcriptional regulator of plasma cell maturation. Further, our atlas is a reference map to understand alterations observed in disease. Here, we discover immune-phenotype plasticity in tumoral cells and microenvironment shifts of mantle cell lymphomas (MCL). To facilitate such reference-based analysis, we develop HCATonsilData and SLOcatoR, a computational framework that provides programmatic and modular access to our dataset; and allows the straightforward annotation of future single-cell profiles from secondary lymphoid organs.

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Section: Resultsmentioning

confidence: 99%

An Atlas of Cells in the Human Tonsil

Massoni-Badosa

Soler-Vila

Aguilar-Fernández

et al. 2022

Preprint

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“…Many different factors can shape CD4 + T cell activation and differentiation, including both TCR and OX40/OX40L signaling [ 24 , 25 , 26 ]. To further explore the importance of OX40/OX40L signaling in the pathogenesis of RA, we established a collagen-induced arthritis (CIA) model by using OX40 −/− mice.…”

Section: Resultsmentioning

confidence: 99%

Synovial Macrophages Expression of OX40L Is Required for Follicular Helper T Cells Differentiation in the Joint Microenvironment

Cai

Zhang

Ren

et al. 2022

Cells

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Signaling via the OX40/OX40L axis plays a key role in CD4+ T cell development, and OX40L expression is primarily restricted to antigen-presenting cells (APCs). This study was designed to assess the role of APC-mediated OX40L expression in the context of the development of rheumatoid arthritis (RA)-associated CD4+ T cell subsets. For these analyses, clinical samples were harvested from patients with osteoarthritis and RA, with additional analyses performed using OX40−/− mice and mice harboring monocyte/macrophage-specific deletions of OX40L. Together, these analyses revealed tissue-specific roles for OX40/OX40L signaling in RA. Specifically, higher levels of synovial macrophage OX40L expression were associated with the enhanced development of T follicular helper cells in the joint microenvironment, thereby contributing to the pathogenesis of RA. This Tfh differentiation was found to be OX40/OX40L-dependent in this synovial setting. Overall, these results indicate that the expression of OX40L by synovia macrophages is necessary to support Tfh differentiation in the joint tissues, thus offering new insight regarding the etiological basis for RA progression.

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“…They are defined by their expression of the transcription factor B cell lymphoma 6 (Bcl6) and several cell surface markers including CXCR5, PD1, and ICOS [18] , [19] . They play a critical role in protective immunity by providing continuous co-stimulatory help to B cells and driving high-affinity antibody production against pathogens, but they have also been implicated in pathogenesis of some autoimmune diseases [20] . Recently, it was reported that elevated frequencies of activated TFH cells were found in the blood of patients with non-severe COVID-19 symptoms [21] , [22] .…”

Section: Introductionmentioning

confidence: 99%