bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human 60-kDa Heat Shock Protein Is a Target Autoantigen of T Cells Derived from Atherosclerotic Plaques
Authors: Benagiano Marisa , D’Elios Mario M. , Amedei Amedeo , Azzurri Annalisa , van der Zee Ruurd , Ciervo Alessandra , Rombolà Gianni , Romagnani Sergio , Cassone Antonio , Del Prete Gianfranco 
Published: April 2014

Abstract
Epidemiological studies suggest the potential importance of an inflammatory component in atherosclerosis and support the hypothesis that immune responses to Ags of pathogens cross-react with homologous host proteins due to molecular mimicry. Protein candidates involved may be the stress-induced proteins known as heat shock proteins (HSP). In this study, we report that atherosclerotic plaques harbor in vivo-activated CD4+ T cells that recognize the human 60-kDa HSP. Such in vivo-activated 60-kDa HSP-specific T cells are not detectable in the peripheral blood. In patients with positive serology and PCR for Chlamydia pneumoniae DNA, but not in patients negative for both, most of plaque-derived T cells specific for human 60-kDa HSP also recognized the C. pneumoniae 60-kDa HSP. We characterized the submolecular specificity of such 60-kDa HSP-specific plaque-derived T cells and identified both the self- and cross-reactive epitopes of that autoantigen. On challenge with human 60-kDa HSP, most of the plaque-derived T cells expressed Th type 1 functions, including cytotoxicity and help for monocyte tissue factor production. We suggest that arterial endothelial cells, undergoing classical atherosclerosis risk factors and conditioned by Th type 1 cytokines, express self 60-kDa HSP, which becomes target for both autoreactive T cells and cross-reactive T cells to microbial 60-kDa HSP via a mechanism of molecular mimicry. This hypothesis is in agreement with the notion that immunization with HSP exacerbates atherosclerosis, whereas immunosuppression and T cell depletion prevent the formation of arteriosclerotic lesions in experimental animals.
Nucleotide-Binding Oligomerization Domain-2 Modulates Specific TLR Pathways for the Induction of Cytokine Release
Authors: Netea Mihai G. , Ferwerda Gerben , de Jong Dirk J. , Jansen Trees , Jacobs Liesbeth , Kramer Matthijs , Naber Ton H. J. , Drenth Joost P. H. , Girardin Stephen E. , Jan Kullberg Bart , Adema Gosse J. , Van der Meer Jos W. M. 
Published: April 2014

Abstract
The recognition of peptidoglycan by cells of the innate immune system has been controversial; both TLR2 and nucleotide-binding oligomerization domain-2 (NOD2) have been implicated in this process. In the present study we demonstrate that although NOD2 is required for recognition of peptidoglycan, this leads to strong synergistic effects on TLR2-mediated production of both pro- and anti-inflammatory cytokines. Defective IL-10 production in patients with Crohn’s disease bearing loss of function mutations of NOD2 may lead to overwhelming inflammation due to a subsequent Th1 bias. In addition to the potentiation of TLR2 effects, NOD2 is a modulator of signals transmitted through TLR4 and TLR3, but not through TLR5, TLR9, or TLR7. Thus, interaction between NOD2 and specific TLR pathways may represent an important modulatory mechanism of innate immune responses.
Cutting Edge: Atopy Promotes Th2 Responses to Alloantigens and Increases the Incidence and Tempo of Corneal Allograft Rejection
Authors: Beauregard Clay , Stevens Christina , Mayhew Elizabeth , Niederkorn Jerry Y. 
Published: April 2014

Abstract
A large body of evidence suggests that corneal allograft rejection is mediated by a type 1 Th cell response and that deviation toward type 2 immunity favors graft survival. However, clinical observations indicate that patients with severe ocular allergies have increased risk of corneal allograft rejection. We used a mouse model of atopic conjunctivitis to evaluate the effects of Th2 immune deviation on corneal allograft survival and possible mechanisms of graft rejection. Our results reveal the following novel findings: 1) atopic conjunctivitis promotes systemic Th2 immune responses to corneal graft donor alloantigens; 2) corneal allografts in atopic host eyes have an increased incidence and swifter tempo of rejection; 3) increased rejection is associated with alterations in systemic T cell-mediated responses to donor alloantigens; and 4) corneal allograft rejection in atopic hosts does not require the direct involvement of infiltrating eosinophils.
Cutting Edge: Silencing Suppressor of Cytokine Signaling 3 Expression in Dendritic Cells Turns CD28-Ig from Immune Adjuvant to Suppressant
Authors: Orabona Ciriana , Belladonna Maria Laura , Vacca Carmine , Bianchi Roberta , Fallarino Francesca , Volpi Claudia , Gizzi Stefania , Fioretti Maria Cristina , Grohmann Ursula , Puccetti Paolo 
Published: April 2014

Abstract
CTLA-4-Ig and CD28-Ig are both agonist ligands of B7 coreceptor molecules on mouse dendritic cells (DCs), yet they bias the downstream response in opposite directions, and CTLA-4-Ig promotes tolerance, whereas CD28-Ig favors the onset of immunity. Although B7 engagement by either ligand leads to a mixed cytokine response, a dominant IL-6 production in response to CD28-Ig prevents the IFN-γ-driven induction of immunosuppressive tryptophan catabolism mediated by IDO. In the present study, we show that silencing the expression of suppressor of cytokine signaling 3 (SOCS3) in DCs by RNA interference renders CD28-Ig capable of activating IDO, likely as a result of unrestrained IFN-γ signaling and IFN-γ-like actions of IL-6. Thus, in the absence of SOCS3, CD28-Ig becomes immunosuppressive and mimics the action of CTLA-4-Ig on tryptophan catabolism.
Cutting Edge: Expression of IL-1 Receptor-Associated Kinase-4 (IRAK-4) Proteins with Mutations Identified in a Patient with Recurrent Bacterial Infections Alters Normal IRAK-4 Interaction with Components of the IL-1 Receptor Complex
Authors: Medvedev Andrei E. , Thomas Karen , Awomoyi Agnes , Kuhns Douglas B. , Gallin John I. , Li Xiaoxia , Vogel Stefanie N. 
Published: April 2014

Abstract
In a patient with recurrent bacterial infections and profound hyporesponsiveness to LPS and IL-1, we previously identified two mutations in IL-1R-associated kinase-4 (IRAK-4) that encoded proteins with truncated kinase domains. Overexpression of either of these mutant IRAK-4 variants in HEK293 cells failed to activate endogenous IRAK-1 and suppressed IL-1-induced IRAK-1 kinase activity, in contrast to wild-type (WT) IRAK-4. In this study, interactions of WT and mutant IRAK-4 species with IL-1R, IRAK-1, and MyD88 in HEK293 transfectants were compared. IL-1 induced a strong interaction among the IL-1R, activated IRAK-1, MyD88, and WT, but not mutant, IRAK-4. Truncated IRAK-4 proteins constitutively interacted more strongly with MyD88 and blunted IL-1-induced recruitment of IRAK-1 and MyD88 to the IL-1R. Thus, decreased IL-1-induced association of IRAK-1 and MyD88 with the IL-1RI may result from sequestration of cytoplasmic MyD88 by IRAK-4 mutant proteins. Therefore, mimetics of these truncated IRAK-4 proteins may represent a novel approach to mitigating hyperinflammatory states.
Cutting Edge: Generation of Splenic CD8+ and CD8− Dendritic Cell Equivalents in Fms-Like Tyrosine Kinase 3 Ligand Bone Marrow Cultures
Authors: Naik Shalin H. , Proietto Anna I. , Wilson Nicholas S. , Dakic Aleksandar , Schnorrer Petra , Fuchsberger Martina , Lahoud Mireille H. , O’Keeffe Meredith , Shao Qi-xiang , Chen Wei-feng , Villadangos José A. , Shortman Ken , Wu Li 
Published: April 2014

Abstract
We demonstrate that functional and phenotypic equivalents of mouse splenic CD8+ and CD8− conventional dendritic cell (cDC) subsets can be generated in vitro when bone marrow is cultured with fms-like tyrosine kinase 3 (flt3) ligand. In addition to CD45RAhigh plasmacytoid DC, two distinct CD24high and CD11bhigh cDC subsets were present, and these subsets showed equivalent properties to splenic CD8+ and CD8− cDC, respectively, in the following: 1) surface expression of CD11b, CD24, and signal regulatory protein-α; 2) developmental dependence on, and mRNA expression of, IFN regulatory factor-8; 3) mRNA expression of TLRs and chemokine receptors; 4) production of IL-12 p40/70, IFN-α, MIP-1α, and RANTES in response to TLR ligands; 5) expression of cystatin C; and 6) cross-presentation of exogenous Ag to CD8 T cells. Furthermore, despite lacking surface CD8 expression, the CD24high subset contained CD8 mRNA and up-regulated surface expression when transferred into mice. This culture system allows access to bona fide counterparts of the splenic DC subsets.
EBV and Systemic Lupus Erythematosus: A New Perspective
Authors: Gross Andrew J. , Hochberg Donna , Rand William M. , Thorley-Lawson David A. 
Published: April 2014

Abstract
We have proposed that EBV uses mature B cell biology to access memory B cells as a site of persistent infection. A central feature of this model is that EBV adapts its gene expression profile to the state of the B cell it resides in and that the level of infection is stable over time. This led us to question whether changes in the behavior or regulation of mature B cells would alter the state of EBV persistence. To investigate this, we studied the impact of systemic lupus erythematosus (SLE), a disease characterized by immune dysfunction, on EBV infection. We show that patients with SLE have abnormally high frequencies of EBV-infected cells in their blood, and this is associated with the occurrence of SLE disease flares. Although patients with SLE have frequencies of infected cells comparable to those seen in immunosuppressed patients, in SLE the effect was independent of immunosuppressive therapy. Aberrant expression of viral lytic (BZLF1) and latency (latency membrane proteins 1 and 2a) genes was also detected in the blood of SLE patients. We conclude that the abnormal regulation of EBV infection in SLE patients reflects the sensitivity of the virus to perturbation of the immune system.
Cocaine Modulates Dendritic Cell-Specific C Type Intercellular Adhesion Molecule-3-Grabbing Nonintegrin Expression by Dendritic Cells in HIV-1 Patients
Authors: Nair Madhavan P. N. , Mahajan Supriya D. , Schwartz Stanley A. , Reynolds Jessica , Whitney Robert , Bernstein Zail , Chawda Ram P. , Sykes Don , Hewitt Ross , Hsiao Chiu Bin 
Published: April 2014

Abstract
We report that cocaine may act as cofactor in HIV pathogenesis by increasing dendritic cell-specific C type ICAM-3-grabbing nonintegrin (DC-SIGN) expression on dendritic cells (DC). Our results show that cocaine-using, long-term nonprogressors and normal progressors of HIV infection manifest significantly higher levels of DC-SIGN compared with cocaine-nonusing long-term nonprogressors and normal progressors, respectively. Furthermore, in vitro HIV infection of MDC from normal subjects cultured with cocaine and/or HIV peptides up-regulated DC-SIGN, confirming our in vivo finding. Cocaine, in synergy with HIV peptides, also up-regulates DC-SIGN gene expression by MDC. Furthermore, the cocaine-induced effects were reversed by a D1 receptor antagonist demonstrating the specificity of the reaction. Our results indicate that cocaine exacerbates HIV infection by up-regulating DC-SIGN on DC and these effects are mediated via dysregulation of MAPKs. These data are the first evidence that cocaine up-regulates the expression of DC-SIGN on DC. A better understanding of the role of DC-SIGN in HIV infection may help to design novel therapeutic strategies against the progression of HIV disease in the drug-using population.
Deficiency of the Src Homology Region 2 Domain-Containing Phosphatase 1 (SHP-1) Causes Enrichment of CD4+CD25+ Regulatory T Cells
Authors: Carter Jennifer D. , Calabrese Gina M. , Naganuma Makoto , Lorenz Ulrike 
Published: April 2014

Abstract
A subpopulation of T cells, named regulatory T cells (Treg cells), has been shown to play a key role in tolerance and the prevention of autoimmunity. It is not known how changes in TCR signal strength during thymic T cell development affect the generation of a Treg population. In this study, we took two different strategies to modulate the TCR signal strength: an intrinsic approach, where signaling was enhanced by the loss of a negative regulator, and an extrinsic approach, where signaling strength was altered through variations in the concentrations of the selecting peptide. The tyrosine phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1) is a known negative regulator of TCR-mediated signaling. motheaten mice, lacking expression of SHP-1, showed a 2- to 3-fold increase in the percentage of CD4+CD25+ Treg cells within the CD4+ T cells. Similarly, the percentage of Treg cells was heightened in fetal thymic organ cultures (FTOCs) derived from motheaten mice compared with wild-type FTOCs, thus establishing the thymic origin of these Treg cells. Using FTOCs derived from DO11.10 TCR transgenic mice, we demonstrated that exposure to increasing concentrations of the cognate OVA peptide favored the appearance of Treg cells. Our data suggest that the development of CD4+CD25+ Treg cells is intrinsically different from non-Treg cells and that Treg cells are selectively enriched under conditions of enhanced negative selection. Our data also reveal a key role for the SHP-1-mediated regulation of TCR signal strength in influencing the ratio of Treg vs non-Treg cells.
Role of TLR in B Cell Development: Signaling through TLR4 Promotes B Cell Maturation and Is Inhibited by TLR2
Authors: Hayashi Elize A. , Akira Shizuo , Nobrega Alberto 
Published: April 2014

Abstract
The role of TLR4 in mature B cell activation is well characterized. However, little is known about TLR4 role in B cell development. Here, we analyzed the effects of TLR4 and TLR2 agonists on B cell development using an in vitro model of B cell maturation. Highly purified B220+IgM− B cell precursors from normal C57BL/6 mouse were cultured for 72 h, and B cell maturation in the presence of the TLR agonists was evaluated by expression of IgM, IgD, CD23, and AA4. The addition of LPS or lipid A resulted in a marked increase in the percentage of CD23+ B cells, while Pam3Cys had no effect alone, but inhibited the increase of CD23+ B cell population induced by lipid A or LPS. The TLR4-induced expression of CD23 is not accompanied by full activation of the lymphocyte, as suggested by the absence of activation Ag CD69. Experiments with TLR2-knockout mice confirmed that the inhibitory effects of Pam3Cys depend on the expression of TLR2. We studied the effects of TLR-agonists on early steps of B cell differentiation by analyzing IL-7 responsiveness and phenotype of early B cell precursors: we found that both lipid A and Pam3Cys impaired IL-7-dependent proliferation; however, while lipid A up-regulates B220 surface marker, consistent with a more mature phenotype of the IgM− precursors, Pam3Cys keeps the precursors on a more immature stage. Taken together, our results suggest that TLR4 signaling favors B lymphocyte maturation, whereas TLR2 arrests/retards that process, ascribing new roles for TLRs in B cell physiology.
Analysis of the Role of Negative T Cell Costimulatory Pathways in CD4 and CD8 T Cell-Mediated Alloimmune Responses In Vivo
Authors: Ito Toshiro , Ueno Takuya , Clarkson Michael R. , Yuan Xueli , Jurewicz Mollie M. , Yagita Hideo , Azuma Miyuki , Sharpe Arlene H. , Auchincloss Hugh , Sayegh Mohamed H. , Najafian Nader 
Published: April 2014

Abstract
Negative costimulatory signals mediated via cell surface molecules such as CTLA-4 and programmed death 1 (PD-1) play a critical role in down-modulating immune responses and maintaining peripheral tolerance. However, their role in alloimmune responses remains unclear. This study examined the role of these inhibitory pathways in regulating CD28-dependent and CD28-independent CD4 and CD8 alloreactive T cells in vivo. CTLA-4 blockade accelerated graft rejection in C57BL/6 wild-type recipients and in a proportion of CD4−/− but not CD8−/− recipients of BALB/c hearts. The same treatment led to prompt rejection in CD28−/− and a smaller proportion of CD4−/−CD28−/− mice with no effect in CD8−/−CD28−/− recipients. These results indicate that the CTLA-4:B7 pathway provides a negative signal to alloreactive CD8+ T cells, particularly in the presence of CD28 costimulation. In contrast, PD-1 blockade led to accelerated rejection of heart allografts only in CD28−/− and CD8−/−CD28−/− recipients. Interestingly, PD-1 ligand (PD-L1) blockade led to accelerated rejection in wild-type mice and in all recipients lacking CD28 costimulation. This effect was accompanied by expansion of IFN-γ-producing alloreactive T cells and enhanced generation of effector T cells in rejecting allograft recipients. Thus, the PD-1:PD-L1 pathway down-regulates alloreactive CD4 T cells, particularly in the absence of CD28 costimulation. The differential effects of PD-1 vs PD-L1 blockade support the possible existence of a new receptor other than PD-1 for negative signaling through PD-L1. Furthermore, PD-1:PD-L1 pathway can regulate alloimmune responses independent of an intact CD28/CTLA-4:B7 pathway. Harnessing physiological mechanisms that regulate alloimmunity should lead to development of novel strategies to induce durable and reproducible transplantation tolerance.
Development of Murine Plasmacytoid Dendritic Cells Defined by Increased Expression of an Inhibitory NK Receptor, Ly49Q
Authors: Omatsu Yoshiki , Iyoda Tomonori , Kimura Yukino , Maki Akiko , Ishimori Masaki , Toyama-Sorimachi Noriko , Inaba Kayo 
Published: April 2014

Abstract
Plasmacytoid dendritic cells (PDCs) are defined in mice by a unique combination of markers: CD11c, B220, and Ly6C/G. We have reported previously that PDCs express Ly49Q, a lectin-type killer cell inhibitory receptor. We now find that different expression levels of Ly49Q define sequential developmental stages of PDCs in bone marrow. Although PDCs in spleen and lymph nodes express high levels of Ly49Q, a significant portion of CD11c+B220+ PDCs in bone marrow lack Ly49Q, as well as the CD4 and MHC II. Purified Ly49Q− marrow PDCs spontaneously up-regulate Ly49Q after overnight culture without cell proliferation and acquire most features of typical PDCs in spleen. When exposed to TLR ligands, such as CpG-oligodeoxynucleotide and hemagglutinating virus of Japan (Sendai virus), Ly49Q− PDCs increase CD86 and MHC class II expression but produce less IFN-αβ, IL-6, and IL-12p70 than Ly49Q+ PDCs, although they are able to produce comparable amounts of TNF-α. However, interestingly, Ly49Q− PDCs do not produce TNF-α in response to the TLR2 ligand, Pam3SCK4, whereas Ly49Q+ PDCs did. Therefore, Ly49Q is a new marker to identify a precursor form of PDCs that participates in innate immunity.
Alternative Splicing Generates Putative Soluble CD83 Proteins That Inhibit T Cell Proliferation
Authors: Dudziak Diana , Nimmerjahn Falk , Bornkamm Georg W. , Laux Gerhard 
Published: April 2014

Abstract
CD83 is expressed on mature dendritic cells and activated lymphocytes and has been implicated to play an important role during T cell development in the thymus. In contrast, not much is known about the function of CD83 in the periphery. Soluble forms of CD83 have been detected in the serum, but neither the function nor the mechanism of how these soluble forms of CD83 are generated are fully understood. In this study, we report the identification of four different transcripts of CD83 in unstimulated PBMCs. Sequence analysis demonstrated that the longest form codes for transmembrane CD83 (CD83-TM), whereas the smaller transcripts are splice variants of full-length CD83, coding for putative soluble CD83 proteins. Stimulation of PBMCs with PHA, TNF-α, or LPS leads to the up-regulation of the full-length CD83 transcript and to a strong down-regulation of two of the three smaller transcripts. The smallest CD83 splice product can be translated efficiently into protein, and recombinant soluble CD83 shows a strong inhibitory effect on T cell proliferation in MLRs. Our results suggest that the constitutive production of soluble forms of CD83 under steady-state conditions may have an important function in regulating immune homeostasis.
OX40 Ligand and CD30 Ligand Are Expressed on Adult but Not Neonatal CD4+CD3− Inducer Cells: Evidence That IL-7 Signals Regulate CD30 Ligand but Not OX40 Ligand Expression
Authors: Kim Mi-Yeon , Anderson Graham , White Andrea , Jenkinson Eric , Arlt Wiebke , Martensson Inga-Lill , Erlandsson Lena , Lane Peter J. L. 
Published: April 2014

Abstract
In this report, we have examined the expression of the T cell survival signals, OX40 ligand (OX40L) and CD30 ligand (CD30L) on CD4+CD3−CD11c−B220−IL-7Rα+ inducer cells from birth to adulthood in mice. We found that adult but not neonatal inducer cells expressed high levels of OX40L and CD30L, whereas their expression of TNF-related activation-induced cytokine (TRANCE) and receptor activator of NF-κB (RANK) was comparable. The failure of neonatal inducer cells to express the ligands that rescue T cells helps to explain why exposure to Ag in neonatal life induces tolerance rather than immunity. The expression of OX40L and CD30L on inducer cells increased gradually in the first few weeks of life achieving essentially normal levels around the time mice were weaned. We found that IL-7 signaling through the common cytokine receptor γ-chain was critical for the optimal expression of both TNF-related activation-induced cytokine and CD30L but not OX40L. Furthermore, glucocorticoids, which potently suppress T effector function, did not influence the expression of OX40L and CD30L in the presence of IL-7.
Carcinoembryonic Antigen (CEA) Inhibits NK Killing via Interaction with CEA-Related Cell Adhesion Molecule 1
Authors: Stern Noam , Markel Gal , Arnon Tal I. , Gruda Raizy , Wong Henry , Gray-Owen Scott D. , Mandelboim Ofer 
Published: April 2014

Abstract
The NK killing activity is regulated by activating and inhibitory NK receptors. All of the activating ligands identified so far are either viral or stress-induced proteins. The class I MHC proteins are the ligands for most of the inhibitory NK receptors. However, in the past few years, several receptors have been identified that are able to inhibit NK killing independently of class I MHC recognition. We have previously demonstrated the existence of a novel inhibitory mechanism of NK cell cytotoxicity mediated by the homophilic carcinoembryonic Ag (CEA)-related cell adhesion molecule 1 (CEACAM1) interactions. In this study, we demonstrate that CEACAM1 also interacts heterophilically with the CEA protein. Importantly, we show that these heterophilic interactions of CEA and CEACAM1 inhibit the killing by NK cells. Because CEA is expressed on a wide range of carcinomas and commonly used as tumor marker, these results represent a novel role for the CEA protein enabling the escape of tumor cells from NK-mediated killing. We further characterize, for the first time, the CEACAM1-CEA interactions. Using functional and binding assays, we demonstrate that the N domains of CEACAM1 and CEA are crucial but not sufficient for both the CEACAM1-CEACAM1 homophilic and CEACAM1-CEA heterophilic interactions. Finally, we suggest that the involvement of additional domains beside the N domain in the heterophilic and homophilic interactions is important for regulating the balance between cis and trans interactions.