bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kinetics of Expansion of Epitope-Specific T Cell Responses during Primary HIV-1 Infection
Authors: Turnbull Emma L. , Wong MaiLee , Wang Shuyi , Wei Xiping , Jones Nicola A. , Conrod Karen E. , Aldam Diana , Turner Jo , Pellegrino Pierre , Keele Brandon F. , Williams Ian , Shaw George M. , Borrow Persephone 
Published: May 2009

Abstract
Multiple lines of evidence support a role for CD8+ T cells in control of acute/early HIV replication; however, features of the primary HIV-specific CD8+ T cell response that may impact on the efficiency of containment of early viral replication remain poorly defined. In this study, we performed a novel, comprehensive analysis of the kinetics of expansion of components of the HIV-specific CD8+ T cell response in 21 acutely infected individuals. Epitope-specific T cell responses expanded asynchronously during primary infection in all subjects. The most rapidly expanded responses peaked as early as 5 days following symptomatic presentation and were typically of very limited epitope breadth. Responses of additional specificities expanded and contracted in subsequent waves, resulting in successive shifts in the epitope immunodominance hierarchy over time. Sequence variation and escape were temporally associated with the decline in magnitude of only a subset of T cell responses, suggesting that other factors such as Ag load and T cell exhaustion may play a role in driving the contraction of HIV-specific T cell responses. These observations document the preferential expansion of CD8+ T cells recognizing a subset of epitopes during the viral burst in acute HIV-1 infection and suggest that the nature of the initial, very rapidly expanded T cell response may influence the efficiency with which viral replication is contained in acute/early HIV infection.
MFG-E8 Attenuates Intestinal Inflammation in Murine Experimental Colitis by Modulating Osteopontin-Dependent αvβ3 Integrin Signaling
Authors: Aziz Md. Monowar , Ishihara Shunji , Mishima Yoshiyuki , Oshima Naoki , Moriyama Ichiro , Yuki Takafumi , Kadowaki Yasunori , Rumi Mohammad Azharul Karim , Amano Yuji , Kinoshita Yoshikazu 
Published: May 2009

Abstract
MFG-E8 (milk fat globule-epidermal growth factor 8) deficiency is strongly associated with acquisition of immune-mediated disorders due to the loss of tissue homeostasis. However, comparatively little is known regarding its functions in gastrointestinal tract disorders, in which immune homeostasis is a major concern. Herein, we report altered MFG-E8 expression in inflamed colons during the acute phase of murine experimental colitis and found that treatment with recombinant MFG-E8, but not its arginine-glycine-aspartate mutant counterpart, ameliorated colitis by reducing inflammation and improving disease parameters. To reveal the MFG-E8-mediated antiinflammatory mechanism, we employed an in vitro system, which showed the down-regulation of NF-κB in an LPS-dependent manner. Additionally, MFG-E8 altered αvβ3 integrin-mediated focal adhesion kinase phosphorylation by impeding the binding of one of its potent ligands osteopontin, which becomes activated during colitis. Taken together, our results indicated that MFG-E8 has a novel therapeutic potential for treatment of colitis.
PI3K Links NKG2D Signaling to a CrkL Pathway Involved in Natural Killer Cell Adhesion, Polarity, and Granule Secretion
Authors: Segovis Colin M. , Schoon Renee A. , Dick Christopher J. , Nacusi Lucas P. , Leibson Paul J. , Billadeau Daniel D. 
Published: May 2009

Abstract
The NK cell-activating receptor NKG2D plays a critical role in the destruction of malignant cells, but many of the cell-signaling mechanisms governing NKG2D-mediated cellular cytotoxicity are unknown. We have identified an NKG2D-mediated signaling pathway that governs both conjugate formation and cytotoxic granule polarization. We demonstrate that an interaction between the regulatory subunit of PI3K, p85, and the adaptor protein CrkL is required for efficient NKG2D-mediated cellular cytotoxicity. We show decreased NK cell-target cell conjugate formation in NK cells treated with PI3K inhibitors or depleted of CrkL. Independent of adhesion, we find that microtubule organization center polarization toward target cells expressing the NKG2D ligand MICA or toward anti-NKG2D-coated beads is impaired in the absence of CrkL. Ab-stimulated granule release is also impaired in NK cells depleted of CrkL. Furthermore, our data indicate that the small Ras family GTPase Rap1 is activated downstream of NKG2D engagement in a PI3K- and CrkL-dependent manner and is required for conjugate formation, MTOC (microtubule organizing center) polarization, and NKG2D-dependent cellular cytotoxicity. Taken together, our data identify an NKG2D-activated signaling pathway that collectively orchestrates NK cell adhesion, cell polarization, and granule release.
Costimulation Modulation Uncouples Protection from Immunopathology in Memory T Cell Responses to Influenza Virus
Authors: Teijaro John R. , Njau Modesta N. , Verhoeven David , Chandran Smita , Nadler Steven G. , Hasday Jeffrey , Farber Donna L. 
Published: May 2009

Abstract
The rapid effector functions and tissue heterogeneity of memory T cells facilitate protective immunity, but they can also promote immunopathology in antiviral immunity, autoimmunity, and transplantation. Modulation of memory T cells is a promising but not yet achieved strategy for inhibiting these deleterious effects. Using an influenza infection model, we demonstrate that memory CD4 T cell-driven secondary responses to influenza challenge result in improved viral clearance yet do not prevent the morbidity associated with viral infection, and they exacerbate cellular recruitment into the lung, compared with primary responses. Inhibiting CD28 costimulation with the approved immunomodulator CTLA4Ig suppressed primary responses in naive mice infected with influenza, but was remarkably curative for memory CD4 T cell-mediated secondary responses to influenza, with reduced immunopathology and enhanced recovery. We demonstrate that CTLA4Ig differentially affects lymphoid and nonlymphoid responses to influenza challenge, inhibiting proliferation and egress of lymphoid naive and memory T cells, while leaving lung-resident memory CD4 T cell responses intact. Our findings reveal the dual nature of memory T cell-mediated secondary responses and suggest costimulation modulation as a novel strategy to optimize antiviral immunity by limiting the memory T cell response to its protective capacities.
Fatty Acyl Structures of Mycobacterium tuberculosis Sulfoglycolipid Govern T Cell Response
Authors: Guiard Julie , Collmann Anthony , Garcia-Alles Luis Fernando , Mourey Lionel , Brando Thérèse , Mori Lucia , Gilleron Martine , Prandi Jacques , De Libero Gennaro , Puzo Germain 
Published: May 2009

Abstract
CD1b-restricted T lymphocytes recognize a large diversity of mycobacterial lipids, which differ in their hydrophilic heads and the structure of their acyl appendages. Both moieties participate in the antigenicity of lipid Ags, but the structural constraints governing binding to CD1b and generation of antigenic CD1b:lipid Ag complexes are still poorly understood. Here, we investigated the structural requirements conferring antigenicity to Mycobacterium tuberculosis sulfoglycolipid Ags using a combination of CD1b:lipid binding and T cell activation assays with both living dendritic cells and plate-bound recombinant soluble CD1b. Comparison of the antigenicity of a panel of synthetic analogs, sharing the same trehalose-sulfate polar head, but differing in the structure of their acyl tails, shows that the number of C-methyl substituents on the fatty acid, the configuration of the chiral centers, and the respective localization of the two different acyl chains on the sugar moiety govern TCR recognition and T lymphocyte activation. These studies have major implications for the design of sulfoglycolipid analogs with potential use as tuberculosis subunit vaccines.
Disruption of Nrf2 Impairs the Resolution of Hyperoxia-Induced Acute Lung Injury and Inflammation in Mice
Authors: Reddy Narsa M. , Kleeberger Steven R. , Kensler Thomas W. , Yamamoto Masayuki , Hassoun Paul M. , Reddy Sekhar P. 
Published: May 2009

Abstract
Aberrant tissue repair and persistent inflammation following oxidant-mediated acute lung injury (ALI) can lead to the development and progression of various pulmonary diseases, but the mechanisms underlying these processes remain unclear. Hyperoxia is widely used in the treatment of pulmonary diseases, but the effects of this oxidant exposure in patients undergoing recovery from ALI are not clearly understood. Nrf2 has emerged as a crucial transcription factor that regulates oxidant stress through the induction of several detoxifying enzymes and other proteins. Using an experimental model of hyperoxia-induced ALI, we have examined the role of oxidant stress in resolving lung injury and inflammation. We found that when exposed to sublethal (72 h) hyperoxia, Nrf2-deficient, but not wild-type mice, succumbed to death during recovery. When both genotypes were exposed to a shorter period of hyperoxia-induced ALI (48 h), the lungs of Nrf2-deficient mice during recovery exhibited persistent cellular injury, impaired alveolar and endothelial cell regeneration, and persistent cellular infiltration by macrophages and lymphocytes. Glutathione (GSH) supplementation in Nrf2-deficient mice immediately after hyperoxia remarkably restored their ability to recover from hyperoxia-induced damage in a manner similar to that of wild-type mice. Thus, the results of the present study indicate that the Nrf2-regulated transcriptional response and, particularly GSH synthesis, is critical for lung tissue repair and the resolution of inflammation in vivo and suggests that a dysfunctional Nrf2-GSH pathway may compromise these processes in vivo.
Efficient Killing of Human Colon Cancer Stem Cells by γδ T Lymphocytes
Authors: Todaro Matilde , D'Asaro Matilde , Caccamo Nadia , Iovino Flora , Francipane Maria Giovanna , Meraviglia Serena , Orlando Valentina , La Mendola Carmela , Gulotta Gaspare , Salerno Alfredo , Dieli Francesco , Stassi Giorgio 
Published: May 2009

Abstract
Colon cancer comprises a small population of cancer stem cells (CSC) that is responsible for tumor maintenance and resistant to cancer therapies, possibly allowing for tumor recapitulation once treatment stops. We previously demonstrated that such chemoresistance is mediated by autocrine production of IL-4 through the up-regulation of antiapoptotic proteins. Several innate and adaptive immune effector cells allow for the recognition and destruction of cancer precursors before they constitute the tumor mass. However, cellular immune-based therapies have not been experimented yet in the population of CSCs. Here, we show that the bisphosphonate zoledronate sensitizes colon CSCs to Vγ9Vδ2 T cell cytotoxicity. Proliferation and production of cytokines (TNF-α and IFN-γ) and cytotoxic and apoptotic molecules (TRAIL and granzymes) were also induced after exposure of Vγ9Vδ2 T cells to sensitized targets. Vγ9Vδ2 T cell cytotoxicity was mediated by the granule exocytosis pathway and was highly dependent on isoprenoid production by of tumor cells. Moreover, CSCs recognition and killing was mainly TCR mediated, whereas NKG2D played a role only when tumor targets expressed several NKG2D ligands. We conclude that intentional activation of Vγ9Vδ2 T cells by zoledronate may substantially increase antitumor activities and represent a novel strategy for colon cancer immunotherapy.
CD45-Mediated Fodrin Cleavage during Galectin-1 T Cell Death Promotes Phagocytic Clearance of Dying Cells
Authors: Pang Mabel , He Jiale , Johnson Pauline , Baum Linda G. 
Published: May 2009

AbstractDisassembly and phagocytic removal of dying cells is critical to maintain immune homeostasis. The factors that regulate fragmentation and uptake of dying lymphocytes are not well understood. Degradation of fodrin, a cytoskeletal linker molecule that attaches CD45 to the actin cytoskeleton, has been described in apoptotic cells, although no specific initiator of fodrin degradation has been identified. CD45 is a glycoprotein receptor for galectin-1, an endogenous lectin that can trigger lymphocyte apoptosis, although CD45 is not required for phosphatidylserine externalization or DNA degradation during galectin-1 death. In this study, we show that fodrin degradation occurs during galectin-1 T cell death and that CD45 is essential for fodrin degradation to occur. In the absence of CD45, or if fodrin degradation is prevented, galectin-1-induced cell death is not accompanied by membrane blebbing, although phosphatidylserine externalization and DNA degradation proceed, indicating that fodrin degradation occurs via a distinct pathway compared with the pathway that leads to these other hallmarks of cell death. Moreover, there is slower phagocytic uptake by macrophages of T cells in which fodrin degradation is prevented, relative to T cells in which CD45-mediated fodrin degradation occurs. These studies identify a novel role for CD45 in regulating cellular disassembly and promoting phagocytic clearance during galectin-1-induced T cell death.
Cooperation between Molecular Targets of Costimulation in Promoting T Cell Persistence and Tumor Regression
Authors: Zhao Baohua , Song Aihua , Haque Rizwanul , Lei Fengyang , Weiler Lauren , Xiong Xiaofang , Wu Yuzhang , Croft Michael , Song Jianxun 
Published: May 2009

Abstract
Costimulation regulates multiple cellular processes of T cells inducing proliferation, expansion, and survival. The molecular targets of costimulation might then be useful to augment T cell activities. Two defined targets of costimulatory signals in primary T cells are the anti-apoptotic bcl-2 family molecule Bcl-xL, and survivin, an inhibitor of apoptosis family member that might regulate both cell division and survival. However, the relative importance of, and relationship between, these molecules in primary T cells is not clear. To understand whether they have overlapping or cooperative functions, we used retrovirus-mediated transduction to introduce Bcl-xL and survivin separately, or together linked by a 2A picornavirus self-cleaving peptide, into Ag-responding CD8+ T cells. We found that CD8+ effector T cells expressing both Bcl-xL and survivin strongly expanded at an early stage and had a long-term survival advantage over cells transduced with either molecule alone. In vivo, with response to tumor-expressed Ag following adoptive T cell transfer, Ag-reactive CD8+ T cells expressing both Bcl-xL and survivin displayed greatly enhanced tumor protective activity compared with CD8+ T cells expressing either molecule introduced separately. These results indicate that Bcl-xL and survivin can critically contribute in a cooperative, nonredundant manner to augment the accumulation and persistence of CD8+ T cells following encounter with Ag. The data provide new insights into why costimulatory signals might need to be sustained over time and suggest a potential novel approach to augment cellular immunotherapy for cancer.
In Situ IL-12/23p40 Production during Mycobacterial Infection Is Sustained by CD11bhigh Dendritic Cells Localized in Tissue Sites Distinct from Those Harboring Bacilli
Authors: Rothfuchs Antonio Gigliotti , Egen Jackson G. , Feng Carl G. , Antonelli Lis R. V. , Bafica Andre , Winter Nathalie , Locksley Richard M. , Sher Alan 
Published: May 2009

Abstract
Although IL-12/23p40 is known to play a major role in host resistance to Mycobacterium spp, the cellular source, tissue localization, and regulation of p40 production during mycobacterial infection in vivo has been unclear. In this study, we used IL-12/23p40eYFP (yet40) reporter mice to track expression of the cytokine following Mycobacterium bovis bacillus Calmette-Guérin (BCG) infection. We found that in spleens of these mice, p40 production is initiated by a transient burst from CD11blowCD11c+ dendritic cells (DC) which are later replaced at the onset of granuloma formation by CD11bhighCD11c+ DC as the major source of the cytokine. The latter subset was also found to be the key producer of DC-derived p40 in nonlymphoid tissue and in both spleen and liver optimal production of the cytokine was regulated by endogenous TNF-α. Although BCG and p40-expressing DC were both observed in splenic white pulp, p40+ DC rarely colocalized with bacilli. Indeed, in vitro flow cytometry and confocal microscopy indicated that the presence of intracellular bacteria is not required for p40 production by DC and Transwell experiments confirmed that soluble mycobacterial components are sufficient for inducing cytokine expression by these cells. Moreover, when stimulated with LPS, DC directly infected with BCG showed impaired IL-12p40 production in vitro. Together, our findings establish CD11bhigh DC as a major source of IL-12/23p40 during mycobacterial infection in situ and implicate both soluble mycobacterial products and TNF-α in stimulating sustained production of p40 by these cells.
PD-1-Mediated Suppression of IL-2 Production Induces CD8+ T Cell Anergy In Vivo
Authors: Chikuma Shunsuke , Terawaki Seigo , Hayashi Tamon , Nabeshima Ryusuke , Yoshida Takao , Shibayama Shiro , Okazaki Taku , Honjo Tasuku 
Published: May 2009

Abstract
Accumulating evidence suggests that PD-1, an immuno-inhibitory receptor expressed on activated T cells, regulates peripheral T cell tolerance. In particular, PD-1 is involved in the induction and/or maintenance of T cells’ intrinsic unresponsiveness to previously encountered Ags, although the mechanism is yet to be determined. We used a simple experimental model to dissect the mechanism for anergy establishment, in which 2C TCR transgenic rag2−/− PD-1+/+ mice were anergized by a single injection of a cognate peptide. Interestingly, 2C rag2−/− PD-1−/− mice were totally resistant to anergy induction by the same treatment; thus, PD-1 was responsible for anergy induction. Furthermore, PD-1 expression was induced within 24 h of the initial Ag exposure. The establishment of anergy was associated with a marked down-regulation of IL-2 from the CD8+ T cells. In fact, IL-2 blockade resulted in anergy even in 2C rag2−/−PD-1−/− T cells. Furthermore, the complementation of the IL-2 signal in 2C rag2−/− PD-1+/+ mice reversed the anergy induction. We propose that CD8+ T cell anergy is induced by a reduction of cell-autonomous IL-2 synthesis, which is caused by the quick expression of PD-1 in response to Ag stimulation and the subsequent stimulation of this receptor by its ligands on surrounding cells.
Phenotypic and Functional Analyses of KIR3DL1+ and KIR3DS1+ NK Cell Subsets Demonstrate Differential Regulation by Bw4 Molecules and Induced KIR3DS1 Expression on Stimulated NK Cells
Authors: Morvan Maelig , Willem Catherine , Gagne Katia , Kerdudou Nolwenn , David Gaelle , Sébille Véronique , Folléa Gilles , Bignon Jean-Denis , Retière Christelle 
Published: May 2009

Abstract
Recently, the Z27 mAb was shown to recognize the NK cell-activating receptor KIR3DS1, and several genetic studies suggest that the most probable ligands of KIR3DS1 are HLA class I molecules with the Bw4 motif. Despite these findings, the attempts to establish a functional interaction between KIR3DS1 and its potential ligand have been unsuccessful. Here, we study the proliferation and cytotoxicity of KIR3DS1+ NK cells, compared with KIR3DL1+ NK cells, according to the Bw4+ or Bw4− allogeneic environment. Our results show for the first time that KIR3DS1 expression on NK cells can be induced after exposure to stimulator cells (221, K562, EBV-B cell lines, and B cells), polyinosinic-polycytidylic acid, IL-15, or IL-2. Furthermore, whereas KIR3DL1+ NK cell proliferation and cytotoxicity were inhibited in a Bw4+ but not a Bw4− context, KIR3DS1+ NK cell functions were not influenced by the presence of Bw4 on target cells. Nevertheless, despite the absence of demonstrated regulation of KIR3DS1+ NK cell functions by HLA-Bw4 molecules, we found a higher KIR3DS1+ NK cell frequency and higher levels of KIR3DS1 expression in Bw4+ compared with Bw4− individuals. Altogether, these results suggest that KIR3DS1 does not recognize HLA-Bw4 molecules in a physiological context, and they highlight the induced expression of KIR3DS1 observed on stimulated NK cells and the higher frequency of KIR3DS1+ NK cells in Bw4+ individuals. Because a protective KIR3DS1-Bw4 association has been reported in viral infections, our results further the understanding of the role of KIR3DS1+ NK cells in controlling viral infections.
Dendritic Cells Use Endocytic Pathway for Cross-Priming Class Ib MHC-Restricted CD8αα+TCRαβ+ T Cells with Regulatory Properties
Authors: Smith Trevor R. F. , Tang Xiaolei , Maricic Igor , Garcia Zacarias , Fanchiang Shaohsuan , Kumar Vipin 
Published: May 2009

Abstract
Understanding the mechanisms leading to effective priming of lymphocytes with regulatory properties is crucial for the manipulation of immune responses. CD8αα+TCRαβ+ T cells are a special subset of innate-like lymphocytes that have been shown to be involved in immune regulation. These cells can recognize self-peptides in the context of a class Ib molecule, Qa-1. How self-Ags are processed in the Qa-1 pathway and presented to CD8αα+TCRαβ+ T cells is not understood. In this study we demonstrate a cross-presentation pathway by which bone marrow-derived dendritic cells (DCs) capture apoptotic CD4+ T cells and process and present TCR-derived peptides in the context of Qa-1 to prime CD8αα+TCRαβ+ T cells. The priming ability of the DCs is enhanced following TLR signaling using TLR3, TLR4, and TLR9 agonists. DC-mediated cross-presentation is inhibited in the presence of endosomal and proteasomal Ag-processing antagonists. Importantly, DCs loaded with apoptotic T cells prime CD8αα+TCRαβ+ T cells in vivo, which in turn provides protection from CD4+ T cell-mediated autoimmune disease. These data provide a key insight related to processing and presentation of self-Ags in the Qa-1 pathway for priming of CD8αα+TCRαβ+ T cells and have implications for a DC-based immunotherapeutic approach to inflammatory diseases.
CARMA1 Controls an Early Checkpoint in the Thymic Development of FoxP3+ Regulatory T Cells
Authors: Molinero Luciana L. , Yang Jianying , Gajewski Thomas , Abraham Clara , Farrar Michael A. , Alegre Maria-Luisa 
Published: May 2009

Abstract
Natural regulatory T cells (nTregs) that develop in the thymus are essential to limit immune responses and prevent autoimmunity. However, the steps necessary for their thymic development are incompletely understood. The CARMA1/Bcl10/Malt1 (CBM) complex, comprised of adaptors that link the TCR to the transcription factor NF-κB, is required for development of regulatory T cells (Tregs) but not conventional T cells. Current models propose that TCR-NF-κB is needed in a Treg-extrinsic manner for IL-2 production by conventional T cells or in already precommitted Treg precursors for driving IL-2/STAT5 responsiveness and further maturation into Tregs and/or for promoting cell survival. Using CARMA1-knockout mice, our data show instead that the CBM complex is needed in a Treg-intrinsic rather than -extrinsic manner. Constitutive activity of STAT5 or protection from apoptosis by transgenic expression of Bcl2 in developing Tregs is not sufficient to rescue CARMA1-knockout Treg development. Instead, our results demonstrate that the CBM complex controls an early checkpoint in Treg development by enabling generation of thymic precursors of Tregs. These data suggest a modified model of nTreg development in which TCR-CBM-dependent signals are essential to commit immature thymocytes to the nTreg lineage.