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Modulation of natural killer cell functions by interactions between 2B4 and CD48 in cis and in trans.

ABSTRACT: SLAM-related receptors (SRRs) are important modulators of immune cell function. While most SRRs are homophilic, 2B4 (CD244) interacts with CD48, a GPI-anchored protein expressed on many haematopoietic cells. Here we show that natural killer (NK) cell-expressed 2B4 not only binds in trans to CD48 on neighbouring cells but also interacts in cis with CD48 on the same cell. 2B4 uses the same binding site to interact with CD48 in cis and in trans and structural flexibility of 2B4 is necessary for the cis interaction. Furthermore, the cis interaction is sufficient to induce basal phosphorylation of 2B4. However, cis interaction reduces the ability of 2B4 to bind CD48 in trans As a consequence, stimulation-dependent phosphorylation of 2B4 upon binding to CD48 positive target cells is reduced. Interfering with the cis interaction therefore enhanced the lysis of CD48-expressing tumour cells. These data show that the density of 2B4 and CD48 on both the NK cell and the potential target cell modulates NK cell activity.

SUBMITTER: Claus M

PROVIDER: S-EPMC4892432 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Modulation of natural killer cell functions by interactions between 2B4 and CD48 in cis and in trans.

Claus Maren M Wingert Sabine S Watzl Carsten C

Open biology 20160525 5

SLAM-related receptors (SRRs) are important modulators of immune cell function. While most SRRs are homophilic, 2B4 (CD244) interacts with CD48, a GPI-anchored protein expressed on many haematopoietic cells. Here we show that natural killer (NK) cell-expressed 2B4 not only binds in trans to CD48 on neighbouring cells but also interacts in cis with CD48 on the same cell. 2B4 uses the same binding site to interact with CD48 in cis and in trans and structural flexibility of 2B4 is necessary for the ...[more]

PMID: 27249817

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Project description:BackgroundGlioblastoma (GBM) is the most common malignant brain tumor and has "immunologically cold" features. Changing GBM to an "immunologically hot" tumor requires a strong trigger that induces initial immune responses in GBM. Allogeneic natural killer cells (NKCs) have gained considerable attention as promising immunotherapeutic tools against cancer, where gene-edited NKCs would result in effective anti-cancer treatment. The present study focused on the immune checkpoint molecule cytokine-inducible SH2-containing protein (CISH, or CIS) as a critical negative regulator in NKCs.MethodsThe GBM tumor environment featured with immunological aspect was analyzed with Cancer immunogram and GlioVis. We generated human primary CIS-deleted NKCs (NK dCIS) using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) with single guide RNA targeting genome sites on CIS coding exons. The genome-edited NKCs underwent microarray with differential expression analysis and gene set enrichment analysis (GSEA). The anti-GBM activity of the genome-edited NKCs was evaluated by apoptosis induction effects against allogeneic GBM cells and spheroids. We further detected in vivo antitumor effects using xenograft brain tumor mice.ResultsWe successfully induced human CIS-deleted NKCs (NK dCIS) by combining our specific human NKC expansion method available for clinical application and genome editing technology. CIS gene-specific guide RNA/Cas9 protein complex suppressed CIS expression in the expanded NKCs with high expansion efficacy. Comprehensive gene expression analysis demonstrated increased expression of 265 genes and decreased expression of 86 genes in the NK dCIS. Gene set enrichment analysis revealed that the enriched genes were involved in NKC effector functions. Functional analysis revealed that the NK dCIS had increased interferon (IFN)ɤ and tumor necrosis factor (TNF) production. CIS deletion enhanced NKC-mediated apoptosis induction against allogeneic GBM cells and spheroids. Intracranial administration of the allogeneic NKCs prolonged the overall survival of xenograft brain tumor mice. Furthermore, the NK dCIS extended the overall survival of the mice.ConclusionThe findings demonstrated the successful induction of human primary NK dCIS with CRISPR/Cas9 with efficient expansion. CIS deletion enhanced the NKC-mediated anti-tumor effects in allogeneic GBM and could be a promising immunotherapeutic alternative for patients with GBM.

Dataset Information

Modulation of natural killer cell functions by interactions between 2B4 and CD48 in cis and in trans.

Publications

Modulation of natural killer cell functions by interactions between 2B4 and CD48 in cis and in trans.

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