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Sreya Bagchi, Sha Li, Chyung-Ru Wang
Adoptive immunotherapy for cancer treatment is an emerging field of study. Till now, several tumor-derived, peptide-specific T cell responses have been harnessed for treating cancers. However, the contribution of lipid-specific T cells in tumor immunity has been understudied. CD1 molecules, which present self- and foreign lipid antigens to T cells, are divided into group 1 (CD1a, CD1b, and CD1c) and group 2 (CD1d). Although the role of CD1d-restricted natural killer T cells (NKT) in several tumor models has been well established, the contribution of group 1 CD1-restricted T cells in tumor immunity remains obscure due to the lack of group 1 CD1 expression in mice...
2016: Oncoimmunology
John F Trant, Namrata Jain, Delfina M Mazzuca, James T McIntosh, Bo Fan, S M Mansour Haeryfar, Sebastien Lecommandoux, Elizabeth R Gillies
Nanoassemblies presenting multivalent displays of biologically active carbohydrates are of significant interest for a wide array of biomedical applications ranging from drug delivery to immunotherapy. In this study, glycodendron-lipid hybrids were developed as a new and tunable class of dendritic amphiphiles. A modular synthesis was used to prepare dendron-lipid hybrids comprising distearylglycerol and 0 through 4th generation polyester dendrons with peripheral protected amines. Following deprotection of the amines, an isothiocyanate derivative of C-linked α-galactose (α-Gal) was conjugated to the dendron peripheries, affording amphiphiles with 1 to 16 α-Gal moieties...
October 14, 2016: Nanoscale
Silvia Casacuberta-Serra, Carme Costa, Herena Eixarch, María José Mansilla, Sergio López-Estévez, Lluís Martorell, Marta Parés, Xavier Montalban, Carmen Espejo, Jordi Barquinero
Previous work by our group showed that transferring bone marrow cells transduced with a self-antigen induced immune tolerance and ameliorated experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). We also found that following retroviral transduction of murine bone marrow (BM) cells, the majority of cells generated and transduced were myeloid-derived suppressor cells (MDSCs). Here, we aimed to determine whether purified antigen-expressing MDSCs have similar therapeutic effects than those of unfractionated BM, and to investigate their potential mechanisms...
September 28, 2016: Experimental Neurology
Hui-Fern Koay, Nicholas A Gherardin, Anselm Enders, Liyen Loh, Laura K Mackay, Catarina F Almeida, Brendan E Russ, Claudia A Nold-Petry, Marcel F Nold, Sammy Bedoui, Zhenjun Chen, Alexandra J Corbett, Sidonia B G Eckle, Bronwyn Meehan, Yves d'Udekem, Igor E Konstantinov, Martha Lappas, Ligong Liu, Chris C Goodnow, David P Fairlie, Jamie Rossjohn, Mark M Chong, Katherine Kedzierska, Stuart P Berzins, Gabrielle T Belz, James McCluskey, Adam P Uldrich, Dale I Godfrey, Daniel G Pellicci
Mucosal-associated invariant T cells (MAIT cells) detect microbial vitamin B2 derivatives presented by the antigen-presenting molecule MR1. Here we defined three developmental stages and checkpoints for the MAIT cell lineage in humans and mice. Stage 1 and stage 2 MAIT cells predominated in thymus, while stage 3 cells progressively increased in abundance extrathymically. Transition through each checkpoint was regulated by MR1, whereas the final checkpoint that generated mature functional MAIT cells was controlled by multiple factors, including the transcription factor PLZF and microbial colonization...
September 26, 2016: Nature Immunology
Yao Qin, Mei Zhang, Rui-Mei Jiang, Qian Wu, Xin-Yu Xu, Heng Chen, Tao Yang
Recently, pancreatic islet transplantation has been shown to be a viable option for the treatment of type 1 diabetes mellitus. However, immune destruction becomes the major impediment to the clinical application of islet transplantation. Here, we evaluated changes affecting multiple types of immune cells and cytokines in allogeneic islet transplantation immunity after the administration of B10 cells alone and explored the regulatory mechanisms of B10 cells in T cell-mediated allograft rejection. In vitro assays, B10 cells significantly decreased the proliferative capacity of CD4(+)CD25(-) T cells (13...
September 19, 2016: Cellular Immunology
Xilin Zhang, Jun Gu, Li Zhou, Qing-Sheng Mi
T cell immunoglobulin and mucin-4 (TIM-4), mainly expressed on antigen presenting cells, plays a versatile role in immunoregulation. CD1d-restricted invariant natural killer T (iNKT) cells are potent cells involved in the diverse immune responses. It was recently reported that recombinant TIM-4 (rTIM-4) alone enhanced cytokine production in NKT hybridoma, DN32.D3 cells. Hence, we hypothesized that TIM-4 might regulate iNKT cell biology, especially their function of cytokine secretion. For the first time, we identified that TIM-4 was expressed in thymus iNKT cells, and its expression increased upon iNKT cell migration to the secondary lymphoid organs, especially in lymph nodes...
September 20, 2016: Oncotarget
Shinsuke Inuki, Toshihiko Aiba, Natsumi Hirata, Osamu Ichihara, Daisuke Yoshidome, Shunsuke Kita, Katsumi Maenaka, Koichi Fukase, Yukari Fujimoto
The CD1d protein is a nonpolymorphic MHC class I-like protein that controls the activation of natural killer T (NKT) cells through the presentation of self- and foreign-lipid ligands, glycolipids, or phospholipids, leading to the secretion of various cytokines. The CD1d contains a large hydrophobic lipid binding pocket: the A' pocket of CD1d, which recognizes hydrophobic moieties of the ligands, such as long fatty acyl chains. Although lipid-protein interactions typically rely on hydrophobic interactions between lipid chains and the hydrophobic sites of proteins, we showed that the small polar regions located deep inside the hydrophobic A' pocket could be used for the modulation of the lipid binding...
October 4, 2016: ACS Chemical Biology
Zhen-Kui Wang, Li Xue, Tao Wang, Xiu-Jie Wang, Zhi-Qiang Su
Invariant natural killer T (iNKT) cells are a unique subset of T cells that have been implicated in inflammation, atopy, autoimmunity, infections, and cancer. Although iNKT cells have been extensively studied over the past decade, its role in the pathogenesis of ischemic brain injury is still largely unknown. In our study, we determined whether iNKT cells infiltration occur in a mouse model of permanent cerebral ischemia. C57BL6/J male mice were treated with either alpha-galactosylceramide (α-GalCer) or vehicle control before undergoing permanent middle cerebral artery occlusion (pMCAO)...
October 28, 2016: Neuroscience Letters
Meng Zhou, Zhifa Wen, Feng Cheng, Jie Ma, Weixia Li, Hongyan Ren, Yemeng Sheng, Huixia Dong, Liwei Lu, Hong-Ming Hu, Li-Xin Wang
Recent studies have shown that tumor cells can release autophagosomes, which transport a broad array of biologically active molecules with potential modulatory effects on immune cell functions. In this study, we aimed to investigate the role of tumor cells-released autophagosomes (i.e. TRAP) in regulating B cell differentiation and function. TRAPs from murine tumor cell lines were found to induce splenic B cells to differentiate into IL-10-producing regulatory B cells (Bregs) with a distinct phenotype of CD1d(+) CD5(+), which could potently inhibit CD8(+) and CD4(+) T cell responses in IL-10-depedent manner both in vitro and in vivo...
July 2016: Oncoimmunology
Irina V Tiper, Tonya J Webb
Histone deacetylases (HDACs) are a family of enzymes that influence expression of genes implicated in tumor initiation, progression, and anti-tumor responses. In addition to their canonical role in deacetylation of histones, HDACs regulate many non-canonical targets, such as Signal Transducer and Activator of Transcription 3 (STAT3). We hypothesize that tumors use epigenetic mechanisms to dysregulate CD1d-mediated antigen presentation, thereby impairing the ability of natural killer T (NKT) cells to recognize and destroy malignant cells...
September 10, 2016: Cancer Immunology, Immunotherapy: CII
Keng Wang, Lei Tao, Jianbing Su, Yueyang Zhang, Binhua Zou, Yiyuan Wang, Xiaojuan Li
Objective To observe the immunosuppressive function of regulatory B cells (Bregs) in vitro after activated by CpG oligodeoxynucleotide (CpG-ODN) and anti-CD40 mAb. Methods Mice splenic CD5(+)CD1d(high)B cells and CD5(-)CD1d(low)B cells were sorted by flow cytometry. These B cells were first stimulated with CpG-ODN combined with anti-CD40 mAb for 24 hours, and then co-cultured with purified CD4(+)T cells. The interleukin 10 (IL-10) expression in the activated Bregs and other B cell subset, as well as the proliferation and interferon γ (IFN-γ) expression in the CD4(+) T cells activated by anti-CD3 mAb plus anti-CD28 mAb were determined by flow cytometry...
September 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
Matthias Hauptmann, Julia Kolbaum, Stefanie Lilla, David Wozniak, Mohammad Gharaibeh, Bernhard Fleischer, Christian A Keller
T cells are known to contribute to immune protection against scrub typhus, a potentially fatal infection caused by the obligate intracellular bacterium Orientia (O.) tsutsugamushi. However, the contribution of CD8+ T cells to protection and pathogenesis during O. tsutsugamushi infection is still unknown. Using our recently developed BALB/c mouse model that is based on footpad inoculation of the human-pathogenic Karp strain, we show that activated CD8+ T cells infiltrate spleen and lung during the third week of infection...
September 2016: PLoS Neglected Tropical Diseases
Willem van de Veen, Barbara Stanic, Oliver F Wirz, Kirstin Jansen, Anna Globinska, Mübeccel Akdis
Immune tolerance to both self-antigens and innocuous non-self-antigens is essential to protect the host against chronic inflammatory diseases and tissue damage. A wide range of cell types and suppressive molecules are involved in induction and maintenance of tolerance. In addition to their key function in the production of immunoglobulins, B cells can regulate immune responses through their surface molecules and secretion of cytokines. Regulatory B (Breg) cells are characterized by their immunosuppressive capacity, which is often mediated through IL-10 secretion...
September 2016: Journal of Allergy and Clinical Immunology
Pragya Rampuria, Gillian A Lang, T Scott Devera, Casey Gilmore, Jimmy D Ballard, Mark L Lang
Activation of iNKT cells with the CD1d-binding glycolipid adjuvant α-galactosylceramide (α-GC) enhances humoral immunity specific for coadministered T-dependent Ag. However, the relationship between the iNKT cell and the classic T helper (Th) or T follicular helper (Tfh) function following this immunization modality remains unclear. We show that immunization with the C-terminal domain (CTD) of Clostridium difficile toxin B (TcdB), accompanied by activation of iNKT cells with α-GC, led to enhanced production of CTD-specific IgG, which was CD1d- and iNKT cell-dependent and associated with increased neutralization of active TcdB...
August 26, 2016: Journal of Leukocyte Biology
Dorota Kmiec, Shilpa S Iyer, Christina M Stürzel, Daniel Sauter, Beatrice H Hahn, Frank Kirchhoff
UNLABELLED: Human immunodeficiency virus type 1 (HIV-1) groups M, N, O, and P are the result of independent zoonotic transmissions of simian immunodeficiency viruses (SIVs) infecting great apes in Africa. Among these, only Vpu proteins of pandemic HIV-1 group M strains evolved potent activity against the restriction factor tetherin, which inhibits virus release from infected cells. Thus, effective Vpu-mediated tetherin antagonism may have been a prerequisite for the global spread of HIV-1...
2016: MBio
S Kovats, S Turner, A Simmons, T Powe, E Chakravarty, J Alberola-Ila
West Nile virus (WNV) infection is a mosquito-borne zoonosis with increasing prevalence in the United States. WNV infection begins in the skin, and the virus replicates initially in keratinocytes and dendritic cells (DCs). In the skin and cutaneous lymph nodes, infected DCs are likely to interact with invariant natural killer T cells (iNKTs). Bidirectional interactions between DCs and iNKTs amplify the innate immune response to viral infections, thus controlling viral load and regulating adaptive immunity. iNKTs are stimulated by CD1d-bound lipid antigens or activated indirectly by inflammatory cytokines...
November 2016: Clinical and Experimental Immunology
Sara Basbous, Anaïs Levescot, Nathalie Piccirilli, Françoise Brizard, François Guilhot, Lydia Roy, Nicolas Bourmeyster, Jean-Marc Gombert, André Herbelin
CD1d-restricted iNKT cells are believed to play a key role in cancer immune surveillance and are functionally deficient in chronic myeloid leukaemia (CML). Herein, we have hypothesized that this defect might originate from BCR-ABL-dependent dysfunctions in myeloid dendritic cells (mDCs). Indeed, flow cytometry and confocal microscopy revealed that cell surface expression of CD1d was downregulated in CML mDCs, relative to healthy donor (HD) controls. The decreased cell surface display of CD1d could not be ascribed to defective mDC differentiation, as attested by normal expression of HLA-DR and the CD86 maturation marker...
August 11, 2016: Journal of Pathology
Shouxiong Huang, D Branch Moody
The CD1 and MHC systems are specialized for lipid and peptide display, respectively. Here, we review evidence showing how cellular CD1a, CD1b, CD1c, and CD1d proteins capture and display many cellular lipids to T cell receptors (TCRs). Increasing evidence shows that CD1-reactive T cells operate outside two classical immunogenetic concepts derived from the MHC paradigm. First, because CD1 proteins are non-polymorphic in human populations, T cell responses are not restricted to the donor's genetic background...
August 2016: Immunogenetics
Ayano C Kohlgruber, Carlos A Donado, Nelson M LaMarche, Michael B Brenner, Patrick J Brennan
Invariant natural killer T (iNKT) cells are a specialized T cell subset that plays an important role in host defense, orchestrating both innate and adaptive immune effector responses against a variety of microbes. Specific microbial lipids and mammalian self lipids displayed by the antigen-presenting molecule CD1d can activate iNKT cells through their semi-invariant αβ T cell receptors (TCRs). iNKT cells also constitutively express receptors for inflammatory cytokines typically secreted by antigen-presenting cells (APCs) after recognition of pathogen-associated molecular patterns (PAMPs), and they can be activated through these cytokine receptors either in combination with TCR signals, or in some cases even in the absence of TCR signaling...
August 2016: Immunogenetics
Pulak Tripathi, Suzanne C Morris, Charles Perkins, Allyson Sholl, Fred D Finkelman, David A Hildeman
Virtual memory (VM) CD8(+) T cells are present in unimmunized mice, yet possess T-cell receptors specific for foreign antigens. To date, VM cells have only been characterized in C57BL/6 mice. Here, we assessed the cytokine requirements for VM cells in C57BL/6 and BALB/c mice. As reported previously, VM cells in C57BL/6 mice rely mostly on IL-15 and marginally on IL-4. In stark contrast, VM cells in BALB/c mice rely substantially on IL-4 and marginally on IL-15. Further, NKT cells are the likely source of IL-4, because CD1d-deficient mice on a BALB/c background have significantly fewer VM cells...
October 2016: European Journal of Immunology
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