Human Body Composition and Immunity: Visceral Adipose Tissue Produces IL-15 and Muscle Strength Inversely Correlates with NK Cell Function in Elderly Humans.
Front Immunol. 2018;9:440
Authors: Al-Attar A, Presnell SR, Clasey JL, Long DE, Walton RG, Sexton M, Starr ME, Kern PA, Peterson CA, Lutz CT
Natural killer (NK) lymphocyte-mediated cytotoxicity and cytokine secretion control infections and cancers, but these crucial activities decline with age. NK cell development, homeostasis, and function require IL-15 and its chaperone, IL-15 receptor alpha (IL-15Rα). Macrophages and dendritic cells (DC) are major sources of these proteins. We had previously postulated that additional IL-15 and IL-15Rα is made by skeletal muscle and adipose tissue. These sources may be important in aging, when IL-15-producing immune cells decline. NK cells circulate through adipose tissue, where they may be exposed to local IL-15. The objectives of this work were to determine (1) if human muscle, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) are sources of IL-15 and IL-15 Rα, and (2) whether any of these tissues correlate with NK cell activity in elderly humans. We first investigated IL-15 and IL-15Rα RNA expression in paired muscle and SAT biopsies from healthy human subjects. Both tissues expressed these transcripts, but IL-15Rα RNA levels were higher in SAT than in skeletal muscle. We also investigated tissue obtained from surgeries and found that SAT and VAT expressed equivalent amounts of IL-15 and IL-15Rα RNA, respectively. Furthermore, stromal vascular fraction cells expressed more IL-15 RNA than did adipocytes. To test if these findings related to circulating IL-15 protein and NK cell function, we tested 50 healthy adults aged > 70 years old. Plasma IL-15 levels significantly correlated with abdominal VAT mass in the entire cohort and in non-obese subjects. However, plasma IL-15 levels did not correlate with skeletal muscle cross-sectional area and correlated inversely with muscle strength. Plasma IL-15 did correlate with NK cell cytotoxic granule exocytosis and with CCL4 (MIP-1β) production in response to NKp46-crosslinking. Additionally, NK cell responses to K562 leukemia cells correlated inversely with muscle strength. With aging, immune function declines while infections, cancers, and deaths increase. We propose that VAT-derived IL-15 and IL-15Rα is a compensatory NK cell support mechanism in elderly humans.
PMID: 29559978 [PubMed]
Effect of IL-18 on the Expansion and Phenotype of Human Natural Killer Cells: Application to Cancer Immunotherapy.
Int J Biol Sci. 2018;14(3):331-340
Authors: Senju H, Kumagai A, Nakamura Y, Yamaguchi H, Nakatomi K, Fukami S, Shiraishi K, Harada Y, Nakamura M, Okamura H, Tanaka Y, Mukae H
When pathogenic stresses are recognized by innate immune cells, inflammasomes are assembled and caspase-1 is activated, resulting in the conversion of pro-IL-18 into mature IL-18. Because natural killer (NK) cells express IL-18 receptors, IL-18 may play roles in immune functions of NK cells. In the present study, we examined the effect of IL-18 on NK cells derived from lung cancer patients and healthy adult volunteers. When peripheral blood NK cells were stimulated with IL-2, the cells formed clusters beginning on day 5-6 and proliferated thereafter, in which the number of NK cells increased by 10-fold in 10 days. When IL-18 was added, cell clusters were observed as early as on day 4 and NK cells proliferated vigorously. On day 10, the expansion rate was 56-fold on average, showing that IL-18 promoted the expansion of NK cells. It was also notable that IL-18 enhanced the expression of CD80, CD86, HLA-DR and HLA-DQ on NK cells, suggesting that IL-18 conferred NK cells an APC-like phenotype. When cellular cytotoxicity was determined, APC-like NK cells efficiently killed tumor cells and anti-tumor activity was augmented by the addition of tumor antigen-specific mAbs. In addition, IFN-γ was produced by APC-like NK cells in response to tumor cells, and the cytokine production was further enhanced by mAbs. Taken together, IL-18 not only promoted the expansion of NK cells, but also changed the phenotype of NK cells. IL-2/IL-18-induced NK cells might, therefore, serve as a bridge between innate immunity and adaptive immunity and be useful for cancer immunotherapy.
PMID: 29559850 [PubMed - in process]
Spatial and Chemical Surface Guidance of NK Cell Cytotoxic Activity.
ACS Appl Mater Interfaces. 2018 Mar 20;:
Authors: Le Saux G, Edri A, Keydar Y, Hadad U, Porgador A, Schvartzman M
Studying of how different signaling pathways spatially integrate in cells requires selective manipulation and control of different transmembrane ligand-receptor pairs at the same time. This work explores a novel method for precisely arranging two arbitrarily chosen ligands on a micron-scale 2D pattern. The approach is based on lithographic patterning of Au and TiO2 films, followed by their selective functionalization with Ni-NTA/histidine and biotin/avidin chemistries, respectively. The selectivity of chemical and biological functionalizations is demonstrated by XPS and immunofluorescence imaging, respectively. This approach is applied to produce the first of their type bi-functional surfaces with controllably positioned ligands for activating receptors of natural killer (NK) immune cells. NK cells were used as a model system to demonstrate the potency of the surface in guiding site-selective cell attachment and activation. Upon applying the suitable ligand or ligand-combination, surfaces guided the appropriate single- or bi-functional attachment and activation. These encouraging results demonstrate the effectiveness of the system as an experimental platform aimed at the comprehensive understanding of the immunological synapse. The great simplicity, modularity and specificity of this approach makes it applicable for a myriad of combinations of other biomolecules and applications, turning it into the "Swiss knife" of bio-interfaces.
PMID: 29557634 [PubMed - as supplied by publisher]
The novel deubiquitinase inhibitor b-AP15 induces direct and NK cell-mediated antitumor effects in human mantle cell lymphoma.
Cancer Immunol Immunother. 2018 Mar 19;:
Authors: Kropp KN, Maurer S, Rothfelder K, Schmied BJ, Clar KL, Schmidt M, Strunz B, Kopp HG, Steinle A, Grünebach F, Rittig SM, Salih HR, Dörfel D
The first therapeutic proteasome inhibitor bortezomib has clinical efficacy in mantle cell lymphoma (MCL) which resulted in its incorporation in treatment algorithms for this disease. Impairment of proteasomal function by bortezomib is mediated via inhibition of the 20S core particle. However, proteasome function can also be modified by targeting upstream components of the ubiquitin-proteasome system. Recently, b-AP15 has been identified as a small molecule achieving proteasome inhibition by targeting the deubiquitinase (DUB) activity of the 19S regulatory subunit and was found to inhibit cancer cell growth in preclinical analyses. In the present study, both direct antitumor effects and the possibility to induce natural killer group 2 member D ligands (NKG2DL) to reinforce NK cell immunity with b-AP15 were investigated to provide a rational basis for clinical evaluation of this novel DUB inhibitor in MCL. Treatment with b-AP15 resulted in reduced viability as well as induction of apoptosis in a time- and dose-dependent manner, which could be attributed to caspase activation in MCL cells. In addition, treatment with b-AP15 differentially induced NKG2DL expression and subsequent NK cell lysis of MCL cells. These results indicate that the DUB inhibitor b-AP15 displays substantial antitumor activity in human MCL and suggest that b-AP15 might be a novel therapeutic option in the treatment of MCL that warrants clinical investigation.
PMID: 29556699 [PubMed - as supplied by publisher]
Abnormal populations and functions of natural killer cells in patients with myelodysplastic syndromes.
Oncol Lett. 2018 Apr;15(4):5497-5504
Authors: Zhang W, Xie X, Mi H, Sun J, Ding S, Li L, Liu H, Wang H, Fu R, Shao Z
Myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by ineffective hematopoiesis that lead to leukemia. Disorders of the immune system serve important functions in the pathophysiology and progression of this disease. Different levels or mechanisms of natural killer (NK) cells in patients with MDS have been measured in previous studies, making it challenging to understand the pathogenesis of NK cytotoxicity. The present study investigated the frequency of NK cell-mediated antibody-dependent cellular cytotoxicity and explored the function of NK cells by their activating receptors, inhibition signals, degranulation and cytotoxicity factors. In the present study, levels of cluster of differentiation (CD)3-CD56+ NK cells, CD16+-expressing NK cells and subset CD56dim NK cells were decreased in the peripheral blood of patients with MDS. Altered expression of NK protein 44, NK group 2 member D, killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) and KIR2DL3 on NK cell effector signaling pathways may trigger tumor cell lysis in patients with MDS. The weak cellular adhesion and decreased cytotoxicity of NK cells may lead to ineffective antitumor activity in MDS. These observations suggested that NK cells may serve as immunological determinants in MDS and may permit the development of NK cell-based immunotherapy for the treatment of patients with MDS.
PMID: 29556297 [PubMed]