bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-15 Transpresentation Augments CD8+ T Cell Activation and Is Required for Optimal Recall Responses by Central Memory CD8+ T Cells
Authors: Kokaji Andy I. , Hockley Deanna L. , Kane Kevin P. 
Published: April 2014

Abstract
Although the adaptive immune system has a remarkable ability to mount rapid recall responses to previously encountered pathogens, the cellular and molecular signals necessary for memory CD8+ T cell reactivation are poorly defined. IL-15 plays a critical role in memory CD8+ T cell survival; however, whether IL-15 is also involved in memory CD8+ T cell reactivation is presently unclear. Using artificial Ag-presenting surfaces prepared on cell-sized microspheres, we specifically addressed the role of IL-15 transpresentation on mouse CD8+ T cell activation in the complete absence of additional stimulatory signals. In this study we demonstrate that transpresented IL-15 is significantly more effective than soluble IL-15 in augmenting anti-CD3ε-induced proliferation and effector molecule expression by CD8+ T cells. Importantly, IL-15 transpresentation and TCR ligation by anti-CD3ε or peptide MHC complexes exhibited synergism in stimulating CD8+ T cell responses. In agreement with previous studies, we found that transpresented IL-15 preferentially stimulated memory phenotype CD8+ T cells; however, in pursuing this further, we found that central memory (TCM) and effector memory (TEM) CD8+ T cells responded differentially to transpresented IL-15. TCM CD8+ T cells undergo Ag-independent proliferation in response to transpresented IL-15 alone, whereas TEM CD8+ T cells are relatively unresponsive to transpresented IL-15. Furthermore, upon Ag-specific stimulation, TCM CD8+ T cell responses are enhanced by IL-15 transpresentation, whereas TEM CD8+ T cell responses are only slightly affected, both in vitro and in vivo. Thus, our findings distinguish the role of IL-15 transpresentation in the stimulation of distinct memory CD8+ T cell subsets, and they also have implications for ex vivo reactivation and expansion of Ag-experienced CD8+ T cells for immunotherapeutic approaches.
Lack of TIM-3 Immunoregulation in Multiple Sclerosis
Authors: Yang Li , Anderson David E. , Kuchroo Juhi , Hafler David A. 
Published: April 2014

Abstract
Multiple sclerosis (MS) is an inflammatory disease of the CNS white matter associated with T cell infiltrates and alterations of immune functions that can be measured in the peripheral immune system. TIM-3 has been identified as a central regulator of IFN-γ-secreting type 1 Th (Th1) cells and immune tolerance. In this study, using a newly generated mAb against human TIM-3, we examined TIM-3 function on ex vivo CD4+ T cells isolated from the circulation of healthy subjects and patients with MS. Blocking TIM-3 during T cell stimulation significantly enhanced IFN-γ secretion in control subjects but had no effect in untreated patients with MS, demonstrating a defect in TIM-3 immunoregulation. Treatment with glatiramer acetate or IFN-β reversed this functional defect. Reduced levels and altered kinetics of T cell TIM-3 expression, which was restored in treated patients, is one mechanism that can explain the loss of TIM-3 regulation of T cell function in untreated patients with MS. These data provide functional, mechanistic data for dysregulated TIM-3 immunoregulation in a human autoimmune disease and suggest that approved therapies for the treatment of MS may function in part by restoring TIM-3 immunoregulation of T cell function.
CD4+CD25+ Regulatory T Cells Specific for a Thymus-Expressed Antigen Prevent the Development of Anaphylaxis to Self
Authors: Scabeni Stefano , Lapilla Marilena , Musio Silvia , Gallo Barbara , Ciusani Emilio , Steinman Lawrence , Mantegazza Renato , Pedotti Rosetta 
Published: April 2014

Abstract
A role for CD4+CD25+ regulatory T cells (Tregs) in the control of allergic diseases has been postulated. We developed a mouse model in which anaphylaxis is induced in SJL mice by immunization and challenge with the fragment of self myelin proteolipid protein (PLP)139–151, that is not expressed in the thymus, but not with fragment 178–191 of the same protein, that is expressed in the thymus. In this study, we show that resistance to anaphylaxis is associated with naturally occurring CD4+CD25+ Tregs specific for the self peptide expressed in the thymus. These cells increase Foxp3 expression upon Ag stimulation and suppress peptide-induced proliferation of CD4+CD25− effector T cells. Depletion of Tregs with anti-CD25 in vivo significantly diminished resistance to anaphylaxis to PLP178–191, suggesting an important role for CD4+CD25+ Tregs in preventing the development of allergic responses to this thymus-expressed peptide. These data indicate that naturally occurring CD4+CD25+ Tregs specific for a peptide expressed under physiological conditions in the thymus are able to suppress the development of a systemic allergic reaction to self.
Autoimmunity to Both Proinsulin and IGRP Is Required for Diabetes in Nonobese Diabetic 8.3 TCR Transgenic Mice
Authors: Krishnamurthy Balasubramanian , Mariana Lina , Gellert Shane A. , Colman Peter G. , Harrison Leonard C. , Lew Andrew M. , Santamaria Pere , Thomas Helen E. , Kay Thomas W. H. 
Published: April 2014

Abstract
T cells specific for proinsulin and islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP) induce diabetes in nonobese diabetic (NOD) mice. TCR transgenic mice with CD8+ T cells specific for IGRP206–214 (NOD8.3 mice) develop accelerated diabetes that requires CD4+ T cell help. We previously showed that immune responses against proinsulin are necessary for IGRP206–214-specific CD8+ T cells to expand. In this study, we show that diabetes development is dramatically reduced in NOD8.3 mice crossed to NOD mice tolerant to proinsulin (NOD-PI mice). This indicates that immunity to proinsulin is even required in the great majority of NOD8.3 mice that have a pre-existing repertoire of IGRP206–214-specific cells. However, protection from diabetes could be overcome by inducing islet inflammation either by a single dose of streptozotocin or anti-CD40 agonist Ab treatment. This suggests that islet inflammation can substitute for proinsulin-specific CD4+ T cell help to activate IGRP206–214-specific T cells.
Impact of Post-Thymic Cellular Longevity on the Development of Age-Associated CD4+ T Cell Defects
Authors: Jones Stephen C. , Clise-Dwyer Karen , Huston Gail , Dibble John , Eaton Sheri , Haynes Laura , Swain Susan L. 
Published: April 2014

AbstractElderly people are at higher risk for infections due to declining cellular and humoral immune responses. Central to this dysfunction is the reduced responsiveness of the naive CD4+ T cell compartment. Previous data from our laboratory suggest that although defects in the aged naive CD4+ T cell response are apparent in recent thymic emigrant populations, additional defects develop during extended post-thymic longevity in the periphery. To further investigate the factors that lead to aging defects, we took advantage of the OT-II TCR-transgenic (Tg) mouse model. We show that because of an apparent superantigen-mediated loss of naive Vβ5+ Tg CD4+ T cells from the periphery of aging OT-II mice, this compartment becomes enriched for cells of reduced post-thymic longevity, resulting in a frequency of recent thymic emigrants in aged mice that is similar to that of young mice. Purification and functional analysis of aged OT-II cells with reduced post-thymic longevity reveal that they have an age-associated decrease in expansion and IL-2 production in response to Ag in vitro. However, the in vivo expansion, IL-2 production, and cognate B cell helper ability of these cells are similar to those of cells from young mice. In contrast, T cells from aged HNT Tg mice demonstrate extended post-thymic longevity and exhibit severe defects in the same in vitro and in vivo models. These data support a correlation between the requirement for increased post-thymic longevity and the development of the most severe naive CD4+ T cell-aging defects.
Selective Roles of MAPKs during the Macrophage Response to IFN-γ
Authors: Valledor Annabel F. , Sánchez-Tilló Ester , Arpa Luis , Park Jin Mo , Caelles Carme , Lloberas Jorge , Celada Antonio 
Published: April 2014

AbstractMacrophages perform essential functions in the infection and resolution of inflammation. IFN-γ is the main endogenous macrophage Th1 type activator. The classical IFN-γ signaling pathway involves activation of Stat-1. However, IFN-γ has also the capability to activate members of the MAPK family. In primary bone marrow-derived macrophages, we have observed strong activation of p38 at early time points of IFN-γ stimulation, whereas weak activation of ERK-1/2 and JNK-1 was detected at a more delayed stage. In parallel, IFN-γ exerted repressive effects on the expression of a number of MAPK phosphatases. By using selective inhibitors and knockout models, we have explored the contributions of MAPK activation to the macrophage response to IFN-γ. Our findings indicate that these kinases regulate IFN-γ-mediated gene expression in a rather selective way: p38 participates mainly in the regulation of the expression of genes required for the innate immune response, including chemokines such as CCL5, CXCL9, and CXCL10; cytokines such as TNF-α; and inducible NO synthase, whereas JNK-1 acts on genes involved in Ag presentation, including CIITA and genes encoding MHC class II molecules. Modest effects were observed for ERK-1/2 in these studies. Interestingly, some of the MAPK-dependent changes in gene expression observed in these studies are based on posttranscriptional regulation of mRNA stability.
Inducing Antitumor T Cell Immunity: Comparative Functional Analysis of Interstitial Versus Langerhans Dendritic Cells in a Human Cell Line Model
Authors: Santegoets Saskia J. A. M. , Bontkes Hetty J. , Stam Anita G. M. , Bhoelan Farien , Ruizendaal Janneke J. , van den Eertwegh Alfons J. M. , Hooijberg Erik , Scheper Rik J. , de Gruijl Tanja D. 
Published: April 2014

AbstractDendritic cells (DC) are increasingly applied as a cellular adjuvant in immunotherapy of cancer. Two major myeloid DC subsets are recognized: interstitial DC (IDC) that infiltrate connective tissues and Langerhans cells (LC) that line epithelial surfaces. Yet, functional differences between IDC and LC remain to be defined. We recently showed that the CD34+ acute myeloid leukemia cell line MUTZ-3 supports differentiation of both DC-SIGN+ IDC and Langerin-positive Birbeck granule-expressing LC. By comparative functional characterization of MUTZ-3 IDC and MUTZ-3 LC, we aimed to elucidate the relative abilities of these two DC subsets to induce a specific T cell response and reveal the more suitable candidate for use as a clinical vehicle of tumor vaccines. Although mature LC and IDC displayed comparable lymph node-homing potential, mature LC showed higher allogeneic T cell stimulatory capacity. Nevertheless, IDC supported the induction of tumor Ag-specific CD8+ T cells at an overall higher efficiency. This might be related to the observed inability of LC to release T cell stimulatory cytokines such as IL-12p70, IL-23, and IL-15. Although this inability did not result in a detectable deviation in the cytokine expression profile of primed T cells, transduction with IL-12p70 significantly improved priming efficiency of LC, and ensured a functional equivalence with IDC in this regard. In conclusion, except for the inability of LC to release distinct type 1 T cell stimulatory cytokines, in vitro function of LC and IDC suggests comparable abilities of both subsets for the in vivo induction of antitumor T cells.
Dendritic Cell-Dependent Inhibition of B Cell Proliferation Requires CD22
Authors: Santos Lorna , Draves Kevin E. , Boton Mark , Grewal Prabhjit K. , Marth Jamey D. , Clark Edward A. 
Published: April 2014

AbstractRecent studies have shown that dendritic cells (DCs) regulate B cell functions. In this study, we report that bone marrow (BM)-derived immature DCs, but not mature DCs, can inhibit BCR-induced proliferation of B cells in a contact-dependent manner. This inhibition is overcome by treatment with BAFF and is dependent on the BCR coreceptor CD22; however, it is not dependent on expression of the CD22 glycan ligand(s) produced by ST6Gal-I sialyltransferase. We found that a second CD22 ligand (CD22L) is expressed on CD11c+ splenic and BM-derived DCs, which does not contain ST6Gal-I-generated sialic acids and which, unlike the B cell-associated CD22L, is resistant to neuraminidase treatment and sodium metaperiodate oxidation. Examination of splenic and BM B cell subsets in CD22 and ST6Gal-I knockout mice revealed that ST6Gal-I-generated B cell CD22L plays a role in splenic B cell development, whereas the maintenance of long-lived mature BM B cells depends only on CD22 and not on α2,6-sialic acids produced by ST6Gal-I. We propose that the two distinct CD22L have different functions. The α2,6-sialic acid-containing glycoprotein is important for splenic B cell subset development, whereas the DC-associated ST6Gal-I-independent CD22L may be required for the maintenance of long-lived mature B cells in the BM.
TRAIL Deficiency Does Not Rescue Impaired CD8+ T Cell Memory Generated in the Absence of CD4+ T Cell Help
Authors: Sacks Jilian A. , Bevan Michael J. 
Published: April 2014

Abstract
Ag-specific CD8+ T cells immunized in the absence of CD4+ T cell help, so-called “unhelped” CD8+ T cells, are defective in function and survival. We investigated the role of the proapoptotic molecule TRAIL in this defect. We first demonstrate that TRAIL does not contribute to the CD8+ T cell response to Listeria monocytogenes strain expressing OVA (LmOVA) in the presence of CD4+ T cells. Secondly, we generated mice doubly deficient in CD4+ T cells and TRAIL and analyzed their CD8+ T cell response to LmOVA. Memory CD8+ T cells in double-deficient mice waned over time and were not protective against rechallenge, similar to their TRAIL-sufficient unhelped counterparts. To avoid the effects of CD4+ T cell deficiency during memory maintenance, and to address whether TRAIL plays a role in the early programming of the CD8+ T cell response, we performed experiments using heterologous prime and early boost immunizations. We did not observe activation-induced cell death of unhelped CD8+ T cells when mice were infected with followed vaccinia virus expressing OVA 9 days later by LmOVA infection. Furthermore, primary immunization of CD4+ T cell-deficient mice with cell-associated Ag followed by LmOVA infection did not reveal a role for TRAIL-mediated activation-induced cell death. Overall, our results suggest that CD4+ T cell help for the CD8+ T cell response is not contingent on the silencing of TRAIL expression and prevention of TRAIL-mediated apoptosis.
Immunodominance in the TCR Repertoire of αTCR Peptide-Specific CD4+ Treg Population That Controls Experimental Autoimmune Encephalomyelitis
Authors: Madakamutil Loui Thomas , Maricic Igor , Sercarz Eli E. , Kumar Vipin 
Published: April 2014

Abstract
Immunodominance in self-Ag-reactive pathogenic CD4+ T cells has been well established in several experimental models. Although it is clear that regulatory lymphocytes (Treg) play a crucial role in the control of autoreactive cells, it is still not clear whether immunodominant CD4+ Treg clones are also involved in control of autoreactivity. We have shown that TCR-peptide-reactive CD4+ and CD8+ Treg play an important role in the spontaneous recovery and resistance from reinduction of experimental autoimmune encephalomyelitis in B10.PL mice. We report, by sequencing of the TCR α- and β-chain associated with CD4+ Treg, that the TCR repertoire is limited and the majority of CD4+ Treg use the TCR Vβ14 and Vα4 gene segments. Interestingly, sequencing and spectratyping data of cloned and polyclonal Treg populations revealed that a dominant public CD4+ Treg clonotype expressing Vβ14-Jβ1.2 with a CDR3 length of 7 aa exists in the naive peripheral repertoire and is expanded during the course of recovery from experimental autoimmune encephalomyelitis. Furthermore, a higher frequency of CD4+ Treg clones in the naive repertoire correlates with less severity and more rapid spontaneous recovery from disease in parental B10.PL or PL/J and (B10.PL × PL/J)F1 mice. These findings suggest that unlike the Ag-nonspecific, diverse TCR repertoire among the CD25+CD4+ Treg population, TCR-peptide-reactive CD4+ Treg involved in negative feedback regulation of autoimmunity use a highly limited TCR V-gene repertoire. Thus, a selective set of immunodominant Treg as well as pathogenic T cell clones can be targeted for potential intervention in autoimmune disease conditions.
Induction of Antitumor Immune Response by Homeostatic Proliferation and CD28 Signaling
Authors: Suzuki Toshihiro , Ogawa Shuhei , Tanabe Kazunari , Tahara Hideaki , Abe Ryo , Kishimoto Hidehiro 
Published: April 2014

AbstractInducing lymphopenia before adoptive cell transfer can improve the antitumor effect of donor immune cells. It was recently reported that lymphopenic conditions can initiate the differentiation of naive T cells into effector cells. Although T cells require a specific “strong” signal via TCR as well as costimulatory signals during Ag-driven differentiation, there has been little evidence to suggest any requirement for costimulatory signaling for the differentiation of naive T cells in a lymphopenic host. In this study, we demonstrate that naive CD8+ T cells are indispensable for induction of antitumor effect, and, in addition to Ag-driven differentiation, CD28 signaling is essential for the differentiation of naive CD8+ T cells into functional effector CTLs during homeostatic proliferation (HP). The systemic administration of IL-2 did not restore the antitumor effect induced by HP in the absence of CD28 signaling. These results suggest that homeostatic cytokines enable CD8+ T cells to expand and survive, and that TCR and the CD28 signal initiate the differentiation of effector functions. A deeper understanding of the mechanisms underlying enhanced induction of the antitumor immune response with accompanying HP may allow us to more precisely induce enhanced immunity with costimulation signaling and the administration of common γ-chain cytokines.
Invariant NKT Cells Promote CD8+ Cytotoxic T Cell Responses by Inducing CD70 Expression on Dendritic Cells
Authors: Taraban Vadim Y. , Martin Sonya , Attfield Kathrine E. , Glennie Martin J. , Elliott Tim , Elewaut Dirk , Van Calenbergh Serge , Linclau Bruno , Al-Shamkhani Aymen 
Published: April 2014

AbstractActivation of invariant NK T (iNKT) cells with the glycolipid α-galactosylceramide promotes CD8+ cytotoxic T cell responses, a property that has been used to enhance the efficacy of antitumor vaccines. Using chimeric mice, we now show that the adjuvant properties of iNKT cells require that CD40 triggering and Ag presentation to CD8+ T cells occur on the same APCs. We demonstrate that injection of α-galactosylceramide triggers CD70 expression on splenic T cell zone dendritic cells and that this is dependent on CD40 signaling. Importantly, we show that blocking the interaction between CD70 and CD27, its costimulatory receptor on T cells, abrogates the ability of iNKT cells to promote a CD8+ T cell response and abolishes the efficacy of α-GalCer as an adjuvant for antitumor vaccines. These results define a key role for CD70 in linking the innate response of iNKT cells to the activation of CD8+ T cells.
Multivectorial Abnormal Cell Migration in the NOD Mouse Thymus
Authors: Mendes-da-Cruz Daniella A. , Smaniotto Salete , Keller Alexandre C. , Dardenne Mireille , Savino Wilson 
Published: April 2014

AbstractWe previously described a fibronectin/VLA-5-dependent impairment of NOD thymocyte migration, correlated with partial thymocyte arrest within thymic perivascular spaces. Yet, NOD thymocytes still emigrate, suggesting the involvement of other cell migration-related alterations. In this context, the aim of this work was to study the role of extracellular matrix ligands, alone or in combination with the chemokine CXCL12, in NOD thymocyte migration. Intrathymic contents of CXCL12, fibronectin, and laminin were evaluated by immunohistochemistry while the expression of corresponding receptors was ascertained by flow cytometry. Thymocyte migration was measured using Transwell chambers and transendothelial migration was evaluated in the same system, but using an endothelial cell monolayer within the chambers. NOD thymocytes express much lower VLA-5 than C57BL/6 thymocytes. This defect was particularly severe in CD4+ thymocytes expressing Foxp3, thus in keeping with the arrest of Foxp3+ cells within the NOD giant perivascular spaces. We observed an enhancement in CXCL12, laminin, and fibronectin deposition and colocalization in the NOD thymus. Furthermore, we detected altered expression of the CXCL12 receptor CXCR4 and the laminin receptor VLA-6, as well as enhanced migratory capacity of NOD thymocytes toward these molecules, combined or alone. Moreover, transendothelial migration of NOD thymocytes was diminished in the presence of exogenous fibronectin. Our data unravel the existence of multiple cell migration-related abnormalities in NOD thymocytes, comprising both down- and up-regulation of specific responses. Although remaining to be experimentally demonstrated, these events may have consequences on the appearance of autoimmunity in NOD mice.
Protein Kinase Cα and ζ Differentially Regulate Death-Inducing Signaling Complex Formation in Cigarette Smoke Extract-Induced Apoptosis
Authors: Park Jeong-Woong , Kim Hong Pyo , Lee Seon-Jin , Wang Xue , Wang Yong , Ifedigbo Emeka , Watkins Simon C. , Ohba Motoi , Ryter Stefan W. , Vyas Yatin M. , Choi Augustine M. K. 
Published: April 2014

AbstractCigarette smoke, a major risk factor in emphysema, causes cell death by incompletely understood mechanisms. Death-inducing signaling complex (DISC) formation is an initial event in Fas-mediated apoptosis. We demonstrate that cigarette smoke extract (CSE) induces DISC formation in human lung fibroblasts (MRC-5) and promotes DISC trafficking from the Golgi complex to membrane lipid rafts. We demonstrate a novel role of protein kinase C (PKC) in the regulation of DISC formation and trafficking. The PKC isoforms, PKCα, ζ, ε, and η, were activated by CSE exposure. Overexpression of wild-type PKCα inhibited, while PKCζ promoted, CSE-induced cell death. Dominant-negative (dn)PKCζ protected against CSE-induced cell death by suppressing DISC formation and caspase-3 activation, while dnPKCα enhanced cell death by promoting these events. DISC formation was augmented by wortmannin, an inhibitor of PI3K. CSE-induced Akt phosphorylation was reduced by dnPKCα, but it was increased by dnPKCζ. Expression of PKCα in vivo inhibited DISC formation, caspase-3/8 activation, lung injury, and cell death after prolonged cigarette smoke exposure, whereas expression of PKCζ promoted caspase-3 activation. In conclusion, CSE-induced DISC formation is differentially regulated by PKCα and PKCζ via the PI3K/Akt pathway. These results suggest that modulation of PKC may have therapeutic potential in the prevention of smoke-related lung injury.