LLT1 and CD161 Expression in Human Germinal Centers Promotes B Cell Activation and CXCR4 Downregulation

Llibre, Alba; López-Macías, Constantino; Marafioti, Teresa; Mehta, Hema; Partridge, Amy; Kanzig, Carina; Rivellese, Felice; Galson, Jacob D.; Walker, L J; Milne, Paul; Phillips, Rodney E.; Kelly, Dominic F.; Freeman, Gordon J.; Shikh, Mohey Eldin El; Klenerman, Paul; Willberg, Christian

doi:10.4049/jimmunol.1502462

Cited by 35 publications

(50 citation statements)

References 72 publications

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“…We screened a wide variety of human cell types and tissues using our novel monoclonal antibody, clone 2H7, and described LLT1 expression in circulating B cells and monocytes. The presence of LLT1 could also be observed in B cells in tonsils, as previously described 6, 9, 21 , but not in Kupffer cells in the liver or alveolar macrophages in the lung. Furthermore, LLT1 could be detected in several healthy human tissues, but it was remarkably prevalent in immune-privileged sites, such as brain, placenta and testes.…”

Section: Introductionsupporting

confidence: 82%

“…We and others have shown the expression of LLT1 in tissue resident germinal centre B cells 6, 9 . We demonstrated that the 2H7 mAb recognises LLT1 on germinal centre B cells, both immunohistologically and by flow cytometry ( Figure 1C) 6 . Thus, the 2H7 mAb is a good tool for studying the distribution of LLT1 in tissue through immunohistochemical staining.…”

Section: Resultsmentioning

confidence: 71%

“…These are the NKp65-Keratinocyte associated C type lectin (KACL), the NKp80-Activated induced C-type lectin (AICL) and the CD161-Lectin-Like Transcript 1 (LLT1), which are involved in skin immunobiology 1 , cross-talk between Natural Killer (NK) cells and monocytes 2 and modulation of T, NK and B cell immune responses 3– 6 , respectively. Amongst these, the CD161-LLT1 pair has been the focus of attention of several recent studies 6– 10 . LLT1 has been described as a multi-functional protein 11 , and to fully elucidate the functional consequences of its interactions with its receptor, CD161, a comprehensive characterisation of LLT1 distribution is needed.…”

Section: Introductionmentioning

confidence: 99%

“…The current published literature presents inconsistencies, which may partially be due to the activation state of the cells tested and the different anti-LLT1 antibodies used. Indeed, LLT1 has been shown to be upregulated upon different forms of activation 6, 12– 15 .…”

Section: Introductionmentioning

confidence: 99%

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Expression of lectin-like transcript-1 in human tissues

et al. 2016

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Background: Receptor-ligand pairs of C-type lectin-like proteins have been shown to play an important role in cross talk between lymphocytes, as well as in immune responses within concrete tissues and structures, such as the skin or the germinal centres. The CD161-Lectin-like Transcript 1 (LLT1) pair has gained particular attention in recent years, yet a detailed analysis of LLT1 distribution in human tissue is lacking. One reason for this is the limited availability and poor characterisation of anti-LLT1 antibodies. Methods: We assessed the staining capabilities of a novel anti-LLT1 antibody clone (2H7), both by immunohistochemistry and flow cytometry, showing its efficiency at LLT1 recognition in both settings. We then analysed LLT1 expression in a wide variety of human tissues. Results: We found LLT1 expression in circulating B cells and monocytes, but not in lung and liver-resident macrophages. We found strikingly high LLT1 expression in immune-privileged sites, such as the brain, placenta and testes, and confirmed the ability of LLT1 to inhibit NK cell function. Conclusions: Overall, this study contributes to the development of efficient tools for the study of LLT1. Moreover, its expression in different healthy human tissues and, particularly, in immune-privileged sites, establishes LLT1 as a good candidate as a regulator of immune responses.

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Section: Introductionsupporting

confidence: 82%

Section: Resultsmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression of lectin-like transcript-1 in human tissues

et al. 2016

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“…Multiple therapeutic possibilities involving CXCR4 have been attempted including monoclonal antibodies [139], the pan-PI3K inhibitor BKM120 [146] and crosslinking of LLT1 [147]. …”

Section: Follicular Lymphomamentioning

confidence: 99%

The role of G protein-coupled receptors in lymphoid malignancies

Nugent

Proia

2017

Cellular Signalling

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B cell lymphoma consists of multiple individual diseases arising throughout the lifespan of B cell development. From pro-B cells in the bone marrow, through circulating mature memory B cells, each stage of B cell development is prone to oncogenic mutation and transformation, which can lead to a corresponding lymphoma. Therapies designed against individual types of lymphoma often target features that differ between malignant cells and the corresponding normal cells from which they arise. These genetic changes between tumor and normal cells can include oncogene activation, tumor suppressor gene repression and modified cell surface receptor expression. G protein-coupled receptors (GPCRs) are an important class of cell surface receptors that represent an ideal target for lymphoma therapeutics. GPCRs bind a wide range of ligands to relay extracellular signals through G protein-mediated signaling cascades. Each lymphoma subgroup expresses a unique pattern of GPCRs and efforts are underway to fully characterize these patterns at the genetic level. Aberrations such as overexpression, deletion and mutation of GPCRs have been characterized as having causative roles in lymphoma and such studies describing GPCRs in B cell lymphomas are summarized here.

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Landscape of gut mucosal immune cells showed gap of follicular or memory B cells into plasma cells in immunological non‐responders

Wang,

Zhen,

Guo

et al. 2024

Clinical & Translational Med

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BackgroundThe gut is an important site for human immunodeficiency virus (HIV) infection and immune responses. The role of gut mucosal immune cells in immune restoration in patients infected with HIV undergoing antiretroviral therapy remains unclear.MethodsIleocytes, including 54 475 immune cells, were obtained from colonoscopic biopsies of five HIV‐negative controls, nine immunological responders (IRs), and three immunological non‐responders (INRs) and were analyzed using single‐cell RNA sequencing. Immunohistochemical assays were performed for validation. The 16S rRNA gene was amplified using PCR in faecal samples to analyze faecal microbiota. Flow cytometry was used to analyze CD4+ T‐cell counts and the activation of T cells.ResultsThis study presents a global transcriptomic profile of the gut mucosal immune cells in patients infected with HIV. Compared with the IRs, the INRs exhibited a lower proportion of gut plasma cells, especially the IGKC+IgA+ plasma cell subpopulation. IGKC+IgA+ plasma cells were negatively associated with enriched f. Prevotellaceae the INRs and negatively correlated with the overactivation of T cells, but they were positively correlated with CD4+ T‐cell counts. The INRs exhibited a higher proportion of B cells than the IRs. Follicular and memory B cells were significantly higher in the INRs. Reduced potential was observed in the differentiation of follicular or memory B cells into gut plasma cells in INRs. In addition, the receptor‐ligand pairs CD74_MIF and CD74_COPA of memory B/ follicular helper T cells were significantly reduced in the INRs, which may hinder the differentiation of memory and follicular B cells into plasma cells.ConclusionsOur study shows that plasma cells are dysregulated in INRs and provides an extensive resource for deciphering the immune pathogenesis of HIV in INRs.Key points An investigation was carried out at the single‐cell‐level to analyze gut mucosal immune cells alterations in PLWH after ART. B cells were significantly increased and plasma cells were significantly decreased in the INRs compared to the IRs and NCs. There are gaps in the transition from gut follicular or memory B cellsinto plasma cells in INRs.

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LLT1 and CD161 Expression in Human Germinal Centers Promotes B Cell Activation and CXCR4 Downregulation

Cited by 35 publications

References 72 publications

Expression of lectin-like transcript-1 in human tissues

Expression of lectin-like transcript-1 in human tissues

The role of G protein-coupled receptors in lymphoid malignancies

Landscape of gut mucosal immune cells showed gap of follicular or memory B cells into plasma cells in immunological non‐responders

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