Natural Killer Cell Functional Activity After 4-1BB Costimulation

Navabi, Shadi Sadat; Doroudchi, Mehrnoosh; Hosseini, Ahmad; Habibagahi, Mojtaba

doi:10.1007/s10753-014-0082-0

Cited by 18 publications

(21 citation statements)

References 28 publications

(35 reference statements)

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“…12 However, the effect of 4-1BB ligation on the cytotoxicity of activated NK cells is controversial, with some studies showing enhancement and others showing inhibition. [37][38][39] Given the ethical limitations on repeated blood sampling from patients with complex medical disorders, future studies with additional patients will be needed to define the role of 4-1BB on NK cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency

Alosaimi

Hoenig

Jaber

et al. 2019

Journal of Allergy and Clinical Immunology

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Background: The tumor TNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a costimulatory signal that enhances CD8 1 T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB is expressed on antigen-presenting cells and EBV-transformed B cells. Objective: We investigated the genetic basis of recurrent sinopulmonary infections, persistent EBV viremia, and EBVinduced lymphoproliferation in 2 unrelated patients. Methods: Whole-exome sequencing, immunoblotting, immunophenotyping, and in vitro assays of lymphocyte and mitochondrial function were performed. Results: The 2 patients shared a homozygous G109S missense mutation in 4-1BB that abolished protein expression and ligand binding. The patients' CD8 1 T cells had reduced proliferation, impaired expression of IFN-g and perforin, and diminished cytotoxicity against allogeneic and HLA-matched EBV-B cells. Mitochondrial biogenesis, membrane potential, and function were significantly reduced in the patients' activated T cells. An inhibitory antibody against 4-1BB recapitulated the patients' defective CD8 1 Tcell activation and cytotoxicity against EBV-infected B cells in vitro. Conclusion: This novel immunodeficiency demonstrates the critical role of 4-1BB costimulation in host immunity against EBV infection.

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Section: Discussionmentioning

confidence: 99%

Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency

Alosaimi

Hoenig

Jaber

et al. 2019

Journal of Allergy and Clinical Immunology

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“…4-1BB costimulation in both mice and humans leads to enhanced T cell-mediated immunity, but the effects are contrasting in human and mouse NK cells. In mice, 4-1BB stimulation leads to enhanced NK cell effector mechanisms, but in humans 4-1BB signaling inhibits NK effector activity and reverse signaling through 4-1BBL on tumor cells can induce IL-10 and TNF-α (77, 118). This is potentially mediated by a putative inhibitory motif 4-1BB LLYIFK in the human cytoplasmic domain that resembles an ITIM domain (76, 77).…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

et al. 2017

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Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population. We have recently demonstrated that the inhibitory checkpoint molecule PD-L1 is upregulated on Tasmanian devil (Sarcophilus harrisii) facial tumor cells in response to the interferon-gamma cytokine. As this could play a role in immune evasion by tumor cells, we performed a thorough comparative analysis of checkpoint molecule protein sequences among Tasmanian devils and eight other species. We report that many of the key signaling motifs and ligand-binding sites in the checkpoint molecules are highly conserved across the estimated 162 million years of evolution since the last common ancestor of placental and non-placental mammals. Specifically, we discovered that the CTLA-4 (MYPPPY) ligand-binding motif and the CTLA-4 (GVYVKM) inhibitory domain are completely conserved across all nine species used in our comparative analysis, suggesting that the function of CTLA-4 is likely conserved in these species. We also found that cysteine residues for intra- and intermolecular disulfide bonds were also highly conserved. For instance, all 20 cysteine residues involved in disulfide bonds in the human 4-1BB molecule were also present in devil 4-1BB. Although many key sequences were conserved, we have also identified immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motifs (ITSMs) in genes and protein domains that have not been previously reported in any species. This checkpoint molecule analysis and review of salient features for each of the molecules presented here can serve as road map for the development of a Tasmanian devil facial tumor disease immunotherapy. Finally, the strategies can be used as a guide for veterinarians, ecologists, and other researchers willing to venture into the nascent field of wild immunology.

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“…However, CD161 is also expressed by Th17 cells as well as MDR1 negative Th17.1 cells (Ramesh et al, 2014). Given the specificity of MDR1 activity on Indeed, this phenomenon has been previously documented (De Maria et al, 2011, Navabi et al, 2015. Furthermore, our experiments also showed that the expression of CD56 and CD161 was down-regulated upon fixation.…”

Section: P a G Esupporting

confidence: 84%

The role of human CD1c+ DCs at activating innate and adaptive immune responses

Mok¹

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In humans, several dendritic cell (DC) subsets have been identified, including the CD1c + DCs, CD141 + DCs and plasmacytoid DC (pDC). It has been suggested that human CD141 + DCs play a role in cross-presentation leading to the induction of cytotoxic T lymphocyte (CTL) responses that are important for immunity against tumours and intracellular pathogens. pDCs are known to be major responders against viruses through secretion of Type I interferons (IFNs).

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Natural Killer Cell Functional Activity After 4-1BB Costimulation

Cited by 18 publications

References 28 publications

Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency

Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency

Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

The role of human CD1c+ DCs at activating innate and adaptive immune responses

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