Rhesus Macaque Activating Killer Immunoglobulin-Like Receptors Associate With Fc Receptor Gamma (FCER1G) and Not With DAP12 Adaptor Proteins Resulting in Stabilized Expression and Enabling Signal Transduction

Hasan, Mahboob; Walter, Lutz

doi:10.3389/fimmu.2021.678964

Cited by 5 publications

(5 citation statements)

References 44 publications

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“…For FCER1G we noticed an increase in rhCMV+ macaques which missed statistical significance ( Figure 4 ). Contrasting human NK cells is the usage of the FCER1G -encoded FcR-gamma protein as the adaptor molecule for activating KIR in rhesus macaques ( 20 ). Therefore, downregulation of this adaptor may not be expected as this would thwart aKIR+ NK cells in rhesus macaques.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to human adaptive NK cells that are further characterized by strongly decreased FCER1G expression ( 9 , 18 ), we found slightly increased transcription of FCER1G in rhCMV+ rhesus macaques as compared to rhCMV- animals ( Figure 4 ). The most probable reason for this difference between human and rhesus macaque adaptive NK cells is that macaques use FCER1G as adapter protein for their stimulatory KIR receptors and not DAP12 ( 20 ) as in human NK cells and, therefore, rely on continued expression of this adaptor protein. However, a report by Shah and colleagues describes a subpopulation of rhesus macaque NK cells that lacks expression of the FCER1G -encoded FCR-gamma adapter protein and expands in rhCMV-infected rhesus macaques ( 67 ).…”

Section: Discussionmentioning

confidence: 99%

“…phenotyping. The collected peripheral blood samples were used to isolate PBMCs (peripheral blood mononuclear cells) following the procedures as described earlier by us (20). In addition, a single spleen sample from autopsy of a euthanized animal (rhCMV+) was obtained from the Pathology Unit.…”

Section: Introductionmentioning

confidence: 99%

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Detailed phenotypic and functional characterization of CMV-associated adaptive NK cells in rhesus macaques

et al. 2022

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Previous research on adaptive NK cells in rhesus macaques suffered from the lack of specific antibodies to differentiate between inhibitory CD94/NKG2A and stimulatory CD94/NKG2C heterodimeric receptors. Recently we reported an expansion of NKG2C receptor-encoding genes in rhesus macaques, but their expression and functional role on primary NK cells remained unknown due to this deficit. Thus, we established monoclonal antibodies 4A8 and 7B1 which show identical specificities and bind to both NKG2C-1 and NKG2C-2 but neither react with NKG2C-3 nor NKG2A on transfected cells. Using a combination of 4A8 and Z199 antibodies in multicolor flow cytometry we detected broad expression (4-73%) of NKG2C-1 and/or NKG2C-2 (NKG2C-1/2) on primary NK cells in rhesus macaques from our breeding colony. Stratifying our data to CMV-positive and CMV-negative animals, we noticed a higher proportion (23-73%) of primary NK cells expressing NKG2C-1/2 in CMV+ as compared to CMV- macaques (4-5%). These NKG2C-1/2-positive NK cells in CMV+ macaques are characterized by lower expression of IL12RB2, ZBTB16, SH2D1B, but not FCER1G, as well as high expression of IFNG, indicating that antibody 4A8 detects CMV-associated adaptive NK cells. Single cell RNA seq data of 4A8-positive NK cells from a rhCMV-positive macaque demonstrated that a high proportion of these adaptive NK cells transcribe in addition to NKG2C-1 and NKG2C-2 also NKG2C-3, but interestingly NKG2A as well. Remarkably, in comparison to NKG2A, NKG2C-1 and in particular NKG2C-2 bind Mamu-E with higher avidity. Primary NK cells exposed to Mamu-E-expressing target cells displayed strong degranulation as well as IFN-gamma expression of 4A8+ adaptive NK cells from rhCMV+ animals. Thus, despite co-expression of inhibitory and stimulatory CD94/NKG2 receptors the higher number of different stimulatory NKG2C receptors and their higher binding avidity to Mamu-E outreach inhibitory signaling via NKG2A. These data demonstrate the evolutionary conservation of the CMV-driven development of NKG2C-positive adaptive NK cells with particular molecular signatures in primates and with changes in gene copy numbers and ligand-binding strength of NKG2C isotypes. Thus, rhesus macaques represent a suitable and valuable nonhuman primate animal model to study the CMV-NKG2C liaison in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Detailed phenotypic and functional characterization of CMV-associated adaptive NK cells in rhesus macaques

et al. 2022

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“…It is a component of the high affinity immunoglobulin E (IgE) receptor involved in the transduction of allergic inflammatory signals in mast cells. It had been proved that it was expressed in monocytes/macrophages of tumor microenvironment 30 , 31 . Studies had shown that the subgroup with higher myeloma expression level had better prognosis.…”

Section: Discussionmentioning

confidence: 99%

A novel tumor immunotherapy-related signature for risk stratification, prognosis prediction, and immune status in hepatocellular carcinoma

Sun,

Xi,

Zhang

et al. 2023

Sci Rep

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Immunotherapy as a strategy to deal with cancer is increasingly being used clinically, especially in hepatocellular carcinoma (HCC). We aim to create an immunotherapy-related signature that can play a role in predicting HCC patients’ survival and therapeutic outcomes. Immunotherapy-related genes were discovered first. Clinical information and gene expression data were extracted from GSE140901. By a series of bioinformatics methods to analyze, overlapping genes were used to build an immunotherapy-related signature that could contribute to predict both the prognosis of people with hepatocellular carcinoma and responder to immune checkpoint blockade therapy of them in TCGA database. Differences of the two groups in immune cell subpopulations were then compared. Furthermore, A nomogram was constructed, based on the immunotherapy-related signature and clinicopathological features, and proved to be highly predictive. Finally, immunohistochemistry assays were performed in HCC tissue and normal tissue adjacent tumors to verify the differences of the four genes expression. As a result of this study, a prognostic protein profile associated with immunotherapy had been created, which could be applied to predict patients' response to immunotherapy and may provide a new perspective as clinicians focus on non-apoptotic treatment for patients with HCC.

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“…As indicated by their nomenclature, KIRs typically have two or three extracellular Ig-like domains (2D or 3D) and either long (L) or short (S) cytoplasmic tails. KIRs with long cytoplasmic tails contain a pair of ITIMs that transduce inhibitory signals, whereas those with short cytoplasmic tails associate with adaptor molecules such as DAP12 or FcεRIγ to transduce activating signals (2, 3). Inhibitory KIRs normally suppress NK cell responses through interactions with MHC class I ligands on the surface of heathy cells.…”

Section: Introductionmentioning

confidence: 99%

MHC class I Ligands of Rhesus Macaque Killer-Cell Immunoglobulin-Like Receptors

Anderson

Sandstrom

Nicholas

et al. 2022

Preprint

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Definition of the MHC class I ligands of rhesus macaque KIRs is fundamental to NK cell biology in this species as an animal model for infectious diseases, reproductive biology and transplantation. To provide a more complete foundation for studying NK cell responses in this species, rhesus macaque KIRs representing common allotypes of lineage II KIR genes were tested for interactions with MHC class I molecules representing diverse Mamu-A, -B, -E, -F, -I and -AG alleles. KIR-MHC class I interactions were identified by co-incubating reporter cell lines bearing chimeric KIR-CD3ζ receptors with target cells expressing individual MHC class I molecules and were corroborated by staining with KIR-Ig Fc domain fusion proteins. Ligands for 10 KIRs of previously unknown specificity were identified that fell into two general categories; interactions with multiple Mamu-Bw4 molecules (KIR3DL04*001, KIR3DL10*002, KIR3DL11*001 and KIR3DS04*003) or with Mamu-A-related molecules (KIR3DL07*004, KIR3DS01*003, KIR3DS02*004, KIR3DS06*002, KIR3DSw07*001 and KIR3DSw09*003). Among the latter group, three KIRs (KIR3DL07*004, KIR3DS02*004 and KIR3DSw09*003) also interacted with Mamu-B*045:03, a hybrid molecule with Mamu-A α1-domain sequences. Both groups include inhibitory and activating receptors that vary in the specificity and strength of their MHC class I interactions. However, whereas the majority of KIRs that recognize Mamu-Bw4 ligands are inhibitory, most of the KIRs that recognize Mamu-A-related ligands are activating. These findings more than double the number of rhesus macaque KIRs with defined MHC class I ligands and reveal an overlapping, but nonredundant, pattern of ligand recognition that supports extensive functional diversification of these receptors.

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Rhesus Macaque Activating Killer Immunoglobulin-Like Receptors Associate With Fc Receptor Gamma (FCER1G) and Not With DAP12 Adaptor Proteins Resulting in Stabilized Expression and Enabling Signal Transduction

Cited by 5 publications

References 44 publications

Detailed phenotypic and functional characterization of CMV-associated adaptive NK cells in rhesus macaques

Detailed phenotypic and functional characterization of CMV-associated adaptive NK cells in rhesus macaques

A novel tumor immunotherapy-related signature for risk stratification, prognosis prediction, and immune status in hepatocellular carcinoma

MHC class I Ligands of Rhesus Macaque Killer-Cell Immunoglobulin-Like Receptors

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