CD200S-POSITIVE GRANULATED LYMPHOID CELLS IN ENDOMETRIUM APPEAR TO BE CD56-POSITIVE UTERINE NK CELLS

Alzheimer’s disease (AD) represents the most common cause of dementia in the elderly. AD is a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. Although the aetiology of AD is not clear, both environmental factors and heritable predisposition may contribute to disease occurrence. In addition, inflammation and immune system alterations have been linked to AD. The prevailing hypothesis as cause of AD is the deposition in the brain of amyloid beta peptides (Aβ). Although Aβ have a role in defending the brain against infections, their accumulation promotes an inflammatory response mediated by microglia and astrocytes. The production of proinflammatory cytokines and other inflammatory mediators such as prostaglandins and complement factors favours the recruitment of peripheral immune cells further promoting neuroinflammation. Age-related inflammation and chronic infection with herpes virus such as cytomegalovirus may also contribute to inflammation in AD patients. Natural killer (NK) cells are innate lymphoid cells involved in host defence against viral infections and tumours. Once activated NK cells secrete cytokines such as IFN-γ and TNF-α and chemokines and exert cytotoxic activity against target cells. In the elderly, changes in NK cell compartment have been described which may contribute to the lower capacity of elderly individuals to respond to pathogens and tumours. Recently, the role of NK cells in the immunopathogenesis of AD is discussed. Although in AD patients the frequency of NK cells is not affected, a high NK cell response to cytokines has been described together with NK cell dysregulation of signalling pathways which is in part involved in this altered behaviour.

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Phenotype of recovering lymphoid cell populations after marrow transplantation.

Journal of Experimental Medicine ◽

10.1084/jem.161.6.1483 ◽

1985 ◽

Vol 161 (6) ◽

pp. 1483-1502 ◽

Cited By ~ 139

Author(s):

K A Ault ◽

J H Antin ◽

D Ginsburg ◽

S H Orkin ◽

J M Rappeport ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Nk Cells ◽

Cell Types ◽

Lymphoid Cells ◽

The Other ◽

Hla Dr ◽

T Cell Antigens ◽

Leu 7

Four patients who received bone marrow transplants were studied sequentially during the posttransplant period to define the pattern of recovering lymphoid cell types. Three patients received T cell-depleted, HLA-matched marrow, and one received untreated marrow from an identical twin. Blood lymphoid cells were labeled with 25 different pairs of monoclonal antibodies. In each sample, one antibody was conjugated to fluorescein and one to phycoerythrin, thus allowing simultaneous assessment of the expression of the two markers using the fluorescence activated cell sorter. A total of 14 antibodies were used, routinely including HLE, Leu-M3, Leu-4, Leu-1, Leu-5, Leu-9, Leu-6, Leu-2, Leu-3, HLA-DR, Leu-7, Leu-11, Leu-15, and Leu-12. Other antibodies were used to further define some populations. This study has allowed us to define six distinct cell types that have appeared in all four patients by day 90 posttransplantation, and which account for 90-100% of all circulating lymphoid cells. These cell types are (a) T helper cells expressing Leu-1, Leu-4, Leu-9, Leu-5, Leu-3, and variable amounts of HLA-DR; (b) T suppressor cells expressing Leu-1, Leu-4, Leu-9, Leu-5, Leu-2, and variable amounts of HLA-DR; (c) B cells expressing Leu-12, B1, HLA-DR, IgD, and IgM, but none of the T cell antigens; (d) an unusual B cell phenotype (Leu-1 B) expressing all of the B cell markers, and also having low amounts of Leu-1, but none of the other T cell antigens; (e) natural killer (NK) cells expressing Leu-11, Leu-15, Leu-5 but none of the other T cell or B cell markers; (f) NK cells expressing Leu-11, Leu-15, Leu-5, and low levels of Leu-2. Both NK types also express Leu-7 on some, but not all cells. The relative frequencies of these cell types varied among the patients and with time, but the striking findings were the presence of relatively few mature T cells, large numbers of NK cells, and the preponderance of the unusual Leu-1 B cell over conventional B cells in all three patients who developed B cells. Sorting experiments confirmed the NK activity of the major NK cell phenotypes, and DNA analysis confirmed that all of the cells studied were of donor origin. In addition, analysis of Ig genes in one patient showed that the Leu-1 B cells were not clonally rearranged.(ABSTRACT TRUNCATED AT 400 WORDS)

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P02.02 Single-cell RNA sequencing of neuroblastoma tumors reveals immunoregulatory interactions as novel targets for immunotherapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-itoc8.14 ◽

2021 ◽

Vol 9 (Suppl 1) ◽

pp. A8.1-A8

Author(s):

J Wienke ◽

WM Kholosy ◽

LL Visser ◽

KM Keller ◽

P Lijnzaad ◽

...

Keyword(s):

T Cells ◽

Nk Cells ◽

Single Cell ◽

Cell Function ◽

Γδ T Cells ◽

Lymphoid Cells ◽

Gene Set Enrichment Analysis ◽

Mycn Amplification ◽

Solid Cancer ◽

Novel Targets

BackgroundImmunotherapy with CAR-T cells, as well as immune checkpoint blockade, show limited clinical efficacy in the pediatric solid cancer neuroblastoma, despite the success in various adult cancers. The lacking efficacy may be due to various immune evasion strategies employed by neuroblastoma tumors, leading to altered functionality of tumor-infiltrating immune cells. We aimed to provide a comprehensive overview of the composition and function of the neuroblastoma immune environment, as well as relevant immunoregulatory interactions (=), to identify novel targets for immunotherapy.Materials and Methods25 tumor samples from 20 patients (17 with high-risk disease, 6 with MYCN amplification), were collected during diagnostic biopsy pre-treatment (n=10) or during resection surgery after induction chemotherapy (n=15). Samples were enzymatically digested, single-cell FACS sorted and sequenced by Cel-Seq2 protocol.ResultsLymphoid cells in the TME consisted of αβ-, γδ-T cells, NK cells and B cells. Among αβ-T cells we identified CD8+ T cells, two functionally distinct clusters of CD4+ T cells, naive-like T cells and FOXP3+ regulatory T cells (Tregs). CD8+ T cells had reduced cytotoxic capacity compared to blood-derived T cells from a reference group. Tregs expressed high levels of PRDM1, LAYN and ICOS, suggesting an effector Treg profile, which is associated with increased inhibitory capacity. Although NK cells expressed the cytotoxic genes NKG7, KLRF1, GNLY, GZMB and PRF1, their expression was significantly lower than in blood-derived reference NK cells. Gene set enrichment analysis (GSEA) confirmed a reduced cytotoxic capacity of tumoral NK cells, which correlated with a decreased expression of activating receptors (r=0.41, p<0.001) and increased TGFβ signaling (r=-0.45, p<0.001). In addition, NK cells highly expressed the heterodimeric receptor KLRC1:KLRD1, which can inhibit NK cell function through HLA-E binding. High HLA-E expression by endothelial, immune and mesenchymal cells confirmed its inhibitory activity in the TME. Within the myeloid compartment we identified various immunosuppressive populations, comprising a cluster of IL10 and VEGFA expressing macrophages, three clusters of M2 differentiated macrophages expressing MMP9 and LGALS3, and dendritic cells with intact antigen presenting capacity, but high expression of numerous genes encoding immunosuppressive molecules such as IDO1, LGALS1, LGALS2, CCL22 and NECTIN2. In MYCN amplified tumors, specifically, we observed even lower cytotoxic capacity of CD8+ T and NK cells. We identified increased TGFB1 expression and defective antigen presentation by myeloid and tumor cells as potential causes for reduced cytotoxicity in MYCN amplified tumors. To identify relevant targets for immunotherapy we constructed an unbiased interaction network, which revealed NECTIN1=CD96 and MIF=CD74 as active immunoregulatory interactions between tumor and T/NK cells, and CD80/CD86=CTLA4, CLEC2D=KLRB1, HLA-E=KLRC1/KLRC2, CD99=PILRA, LGALS9=HAVCR2, and NECTIN2=TIGIT between myeloid and T/NK cells.ConclusionsCytotoxic lymphocytes in the neuroblastoma TME show reduced cytotoxic capacity, likely due to highly immunosuppressive myeloid cells, Tregs and numerous immunoregulatory interactions, which may serve as novel targets for immunotherapy in neuroblastoma.Disclosure InformationJ. Wienke: None. W.M. Kholosy: None. L.L. Visser: None. K.M. Keller: None. P. Lijnzaad: None. T. Margaritis: None. K.P.S. Langenberg: None. R.R. De Krijger: None. F.C.P. Holstege: None. J.J. Molenaar: None.

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Conventional NK cells and ILC1 are partially ablated in the livers of Ncr1iCreTbx21fl/fl mice

Wellcome Open Research ◽

10.12688/wellcomeopenres.11741.2 ◽

2017 ◽

Vol 2 ◽

pp. 39 ◽

Cited By ~ 1

Author(s):

Antonia O. Cuff ◽

Victoria Male

Keyword(s):

Small Intestine ◽

Nk Cells ◽

Mouse Liver ◽

Cell Types ◽

Lymphoid Cells ◽

Disease Models ◽

Type I ◽

Conditional Deletion ◽

Equivalent Reduction

Mouse liver contains both Eomes-dependent conventional natural killer (cNK) cells and Tbet-dependent liver-resident type I innate lymphoid cells (ILC1). In order to better understand the role of ILC1, we attempted to generate mice that would lack liver ILC1, while retaining cNK, by conditional deletion of Tbet in NKp46+ cells. Here we report that the Ncr1iCreTbx21fl/fl mouse has a roughly equivalent reduction in both the cNK and ILC1 compartments of the liver, limiting its utility for investigating the relative contributions of these two cell types in disease models. We also describe the phenotype of these mice with respect to NK cells, ILC1 and NKp46+ ILC3 in the spleen and small intestine lamina propria.

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