bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Thyroid Tumor-Specific Antigen Formed by the Fusion of Two Self Proteins
Authors: Powell Daniel J. , Eisenlohr Laurence C. , Rothstein Jay L. 
Published: April 2014

Abstract
Thyroid epithelial cells frequently express one or more members of the rearranged during transfection/papillary thyroid carcinoma (RET/PTC) fusion oncogene family during early stages of cancer, and fusion gene transcripts have been found in inflammatory conditions of the thyroid such as the autoimmune disease, Hashimoto’s thyroiditis. Because these oncogenes encode chimeric proteins, novel RET/PTC epitopes may be targets of antitumor immune responses. We have been interested in the RET/PTC3 (RP3) fusion protein because this family member is more frequently expressed in radiation-induced and childhood papillary carcinomas than other members of the fusion oncogene family. We hypothesized that the activated kinase of c-RET, in the form of RP3, when expressed in patients with thyroid disease, presents an unusual altered self target for T cell recognition. Interestingly, we find that immunization with mouse RP3 protein can induce a strongly immunogenic response to RP3, although this response is not directed against the peptide comprising the unique fusion region. Rather, the responses are specific for the carboxyl-terminal portion of RP3 that is derived from the self protein c-RET. Furthermore, transplantation of RP3-expressing thyroid tumors into naive mice resulted in leukocytic infiltration, tumor rejection, and induction of RP3-specific T cells. Thus, the somatic fusion of two unrelated self proteins results in the development of a uniquely immunogenic response directed against self epitopes within RP3. These studies may better define the mechanisms controlling the initiation of thyroid-specific immune responses and provide insight into the design of novel molecules for invoking tumor-specific immunity.
Detection of Autoreactive Myelin Proteolipid Protein 139–151-Specific T Cells by Using MHC II (IAs) Tetramers
Authors: Reddy Jayagopala , Bettelli Estelle , Nicholson Lindsay , Waldner Hanspeter , Jang Mei-Huei , Wucherpfennig Kai W. , Kuchroo Vijay K. 
Published: April 2014

AbstractDetection of autoreactive T cells using MHC II tetramers is difficult because of the low affinity of their TCR. We have generated a class II tetramer using the IAs class II molecule combined with an autoantigenic peptide from myelin proteolipid protein (PLP; PLP139–151) and used it to analyze myelin PLP139–151-reactive T cells. Using monomers and multimerized complexes labeled with PE, we confirmed the specificity of the reagent by bioassay and flow cytometry. The IAs tetramers stimulated and stained the PLP139–151-specific 5B6 TCR transgenic T cells and a polyclonal cell line specific for PLP139–151, but not a control T cell line specific for PLP178–191. We used this reagent to optimize conditions to detect low affinity autoreactive T cells. We found that high pH (∼8.0) and neuraminidase treatment enhances the staining capacity of PLP139–151 tetramer without compromising specificity. Furthermore, we found that induction of calcium fluxing by tetramers in T cells may be used as a sensitive measure to detect autoreactive T cells with a low affinity. Taken together, the data show that the tetrameric reagent binds and stimulates PLP139–151-reactive T cells with specificity. This tetrameric reagent will be useful in studying the evolution of PLP139–151-specific repertoire in naive mice and its expansion during the autoimmune disease experimental autoimmune encephalomyelitis.
T Cell Chemokine Receptor Expression in Aging
Authors: Mo Ruran , Chen Jun , Han Yin , Bueno-Cannizares Cecelia , Misek David E. , Lescure Pascal A. , Hanash Samir , Yung Raymond L. 
Published: April 2014

AbstractChanges in chemokine receptor expression are important in determining T cell migration and the subsequent immune response. To better understand the contribution of the chemokine system in immune senescence we determined the effect of aging on CD4+ T cell chemokine receptor function using microarray, RNase protection assays, Western blot, and in vitro chemokine transmigration assays. Freshly isolated CD4+ cells from aged (20–22 mo) mice were found to express a higher level of CCR1, 2, 4, 5, 6, and 8 and CXCR2–5, and a lower level of CCR7 and 9 than those from young (3–4 mo) animals. Caloric restriction partially or completely restored the aging effects on CCR1, 7, and 8 and CXCR2, 4, and 5. The aging-associated differences in chemokine receptor expression cannot be adequately explained by the age-associated shift in the naive/memory or Th1/Th2 profile. CD4+ cells from aged animals have increased chemotactic response to stromal cell-derived factor-1 and macrophage-inflammatory protein-1α, suggesting that the observed chemokine receptor changes have important functional consequences. We propose that the aging-associated changes in T cell chemokine receptor expression may contribute to the different clinical outcome in T cell chemokine receptor-dependent diseases in the elderly.
A Unique Population of Extrathymically Derived αβTCR+CD4−CD8− T Cells with Regulatory Functions Dominates the Mouse Female Genital Tract
Authors: Johansson Martina , Lycke Nils 
Published: April 2014

Abstract
A better understanding of the regulatory role of genital tract T cells is much needed. In this study, we have analyzed the phenotype, distribution, and function of T lymphocytes in the female genital tract of naive, pregnant, or Chlamydia trachomatis-infected C57BL/6 mice. Unexpectedly, we found that the dominant lymphocyte population (70–90%) in the genital tract was that of CD3+αβTCRintCD4−CD8− T cells. Moreover, these cells were CD90low but negative for the classical T cell markers CD2 and CD5. The CD3+B220low cells were NK1.1 negative and found in nude mice as well as in mice deficient for MHC class II, β2-microglobulin, and CD1, indicating extrathymic origin. They dominated the KJ126+Vβ8.2+ population in the genital tract of DO11.10 OVA TCR-transgenic mice, further supporting the idea that the CD3+B220low cells are truly T cells. The function of these T cells appeared not to be associated with immune protection, because only CD4+ and CD8+ T cells increased in the genital tract following chlamydial infection. Notwithstanding this, the infected, as well as the uninfected and the pregnant, uterus was dominated by a high level of the CD3+CD4−CD8−B220low cells. Following in vitro Ag or polyclonal stimulation of the CD3+CD4−CD8−B220low cells, poor proliferative responses were observed. However, these cells strongly impaired splenic T cell proliferation in a cell density-dependent manner. A large fraction of the cells expressed CD25 and produced IFN-γ upon anti-CD3 plus anti-CD28 stimulation, arguing for a strong regulatory role of this novel T cell population in the mouse female genital tract.
Pertussis Toxin Enhances Th1 Responses by Stimulation of Dendritic Cells
Authors: Hou Wanqiu , Wu Yadi , Sun Shuhui , Shi Mude , Sun Yue , Yang Cuihong , Pei Gang , Gu Yundi , Zhong Cuiping , Sun Bing 
Published: April 2014

AbstractPertussis toxin (PTX) has been widely used as an adjuvant to induce Th1-mediated organ-specific autoimmune diseases in animal models. However, the cellular and molecular mechanisms remain to be defined. In this study, we showed that dendritic cells (DC) stimulated with PTX (PTX-DC) were able to substitute for PTX to promote experimental autoimmune uveitis (EAU). EAU induced by PTX-DC revealed a typical Th1 response, characterized by high uveitogenic retinal Ag interphotoreceptor retinoid-binding protein (IRBP)-specific IFN-γ and IL-12 production in the draining lymph nodes, as well as increased levels of anti-IRBP IgG2a and decreased levels of anti-IRBP IgG1 in the serum of IRBP-immunized mice. Furthermore, PTX-DC preferentially induced T cells to produce the Th1 cytokine, IFN-γ. After being stimulated with PTX, DC exhibited up-regulation of MHC class II, CD80, CD86, CD40, and DEC205. PTX-DC had also increased allostimulatory capacity and IL-12 and TNF-α production. Serum IL-12 was increased in naive mice that received PTX-DC i.p. In addition, PTX activated extracellular signal-regulated kinase in DC. Following the inhibition of extracellular signal-regulated kinase signaling, the maturation of PTX-DC was reduced. Subsequently, the ability of PTX-DC to promote IFN-γ production by T cells in vitro and to induce EAU in vivo was blocked. The results suggest that PTX might exert an adjuvant effect on DC to promote their maturation and the production of proinflammatory cytokines, thereby eliciting a Th1 response.
Protective Mucosal Immunity in Aging Is Associated with Functional CD4+ T Cells in Nasopharyngeal-Associated Lymphoreticular Tissue
Authors: Hagiwara Yukari , McGhee Jerry R. , Fujihashi Keiko , Kobayashi Ryoki , Yoshino Naoto , Kataoka Kosuke , Etani Yuri , Kweon Mi-Na , Tamura Shinichi , Kurata Takeshi , Takeda Yoshifumi , Kiyono Hiroshi , Fujihashi Kohtaro 
Published: April 2014

Abstract
Our previous studies showed that mucosal immunity was impaired in 1-year-old mice that had been orally immunized with OVA and native cholera toxin (nCT) as mucosal adjuvant. In this study, we queried whether similar immune dysregulation was also present in mucosal compartments of mice immunized by the nasal route. Both 1-year-old and young adult mice were immunized weekly with three nasal doses of OVA and nCT or with a nontoxic chimeric enterotoxin (mutant cholera toxin-A E112K/B subunit of native labile toxin) from Brevibacillus choshinensis. Elevated levels of OVA-specific IgG Abs in plasma and secretory IgA Abs in mucosal secretions (nasal washes, saliva, and fecal extracts) were noted in both young adult and 1-year-old mice given nCT or chimeric enterotoxin as mucosal adjuvants. Significant levels of OVA-specific CD4+ T cell proliferative and OVA-induced Th1- and Th2-type cytokine responses were noted in cervical lymph nodes and spleen of 1-year-old mice. In this regard, CD4+, CD45RB+ T cells were detected in greater numbers in the nasopharyngeal-associated lymphoreticular tissues of 1-year-old mice than of young adult mice, but the same did not hold true for Peyer’s patches or spleen. One-year-old mice given nasal tetanus toxoid plus the chimeric toxin as adjuvant were protected from lethal challenge with tetanus toxin. This result reinforced our findings that age-associated immune alterations occur first in gut-associated lymphoreticular tissues, and thus nasal delivery of vaccines for nasopharyngeal-associated lymphoreticular tissue-based mucosal immunity offers an attractive possibility to protect the elderly.
Suppressive DNA Vaccination in Myelin Oligodendrocyte Glycoprotein Peptide-Induced Experimental Autoimmune Encephalomyelitis Involves a T1-Biased Immune Response
Authors: Lobell Anna , Weissert Robert , Eltayeb Sana , de Graaf Katrien L. , Wefer Judit , Storch Maria K. , Lassmann Hans , Wigzell Hans , Olsson Tomas 
Published: April 2014

Abstract
Vaccination with DNA encoding a myelin basic protein peptide suppresses Lewis rat experimental autoimmune encephalomyelitis (EAE) induced with the same peptide. Additional myelin proteins, such as myelin oligodendrocyte glycoprotein (MOG), may be important in multiple sclerosis. Here we demonstrate that DNA vaccination also suppresses MOG peptide-induced EAE. MOG91–108 is encephalitogenic in DA rats and MHC-congenic LEW.1AV1 (RT1av1) and LEW.1N (RT1n) rats. We examined the effects of DNA vaccines encoding MOG91–108 in tandem, with or without targeting of the hybrid gene product to IgG. In all investigated rat strains DNA vaccination suppressed clinical signs of EAE. There was no requirement for targeting the gene product to IgG, but T1-promoting CpG DNA motifs in the plasmid backbone of the construct were necessary for efficient DNA vaccination, similar to the case in DNA vaccination in myelin basic protein-induced EAE. We failed to detect any effects on ex vivo MOG-peptide-induced IFN-γ, TNF-α, IL-6, IL-4, IL-10, and brain-derived neurotropic factor expression in splenocytes or CNS-derived lymphocytes. In CNS-derived lymphocytes, Fas ligand expression was down-regulated in DNA-vaccinated rats compared with controls. However, MOG-specific IgG2b responses were enhanced after DNA vaccination. The enhanced IgG2b responses together with the requirement for CpG DNA motifs in the vaccine suggest a protective mechanism involving induction of a T1-biased immune response.
Stat Signals Release Activated Naive Th Cells from an Anergic Checkpoint
Authors: Mohrs Markus , Lacy Dee A. , Locksley Richard M. 
Published: April 2014

Abstract
Activation of naive Th lymphocytes by the TCR and the costimulatory molecule, CD28, is believed to provide competent signals for differentiation to effector cells. Such activated cells proliferated and expressed IL-2, but arrested in an immature state maintained by CTLA-4. Although unresponsive to restimulation by TCR/CD28 alone, restimulation with TCR/CD28 and either Stat4- or Stat6-mediated cytokine signals rescued cells to proliferate and differentiate to the appropriately matched canonical Th subsets. Addition of IL-4 at defined periods revealed that naive T cells were receptive to IL-4-mediated differentiation for up to 3 days after their initial priming. A Stat-dependent anergic checkpoint between clonal expansion and effector cell differentiation may defer the cytokine profile to be instructed at the site of infection, thus preventing the unregulated development of potentially damaging effector cells.
TNF Plays an Essential Role in Tumor Regression after Adoptive Transfer of Perforin/IFN-γ Double Knockout Effector T Cells
Authors: Poehlein Christian H. , Hu Hong-Ming , Yamada Jane , Assmann Ilka , Alvord W. Gregory , Urba Walter J. , Fox Bernard A. 
Published: April 2014

AbstractWe have recently shown that effector T cells (TE) lacking either perforin or IFN-γ are highly effective mediators of tumor regression. To rule out compensation by either mechanism, TE deficient in both perforin and IFN-γ (perforin knockout (PKO)/IFN-γ knockout (GKO)) were generated. The adoptive transfer of PKO/GKO TE mediated complete tumor regression and cured wild-type animals with established pulmonary metastases of the B16BL6-D5 (D5) melanoma cell line. PKO/GKO TE also mediated tumor regression in D5 tumor-bearing PKO, GKO, or PKO/GKO recipients, although in PKO/GKO recipients efficacy was reduced. PKO/GKO TE exhibited tumor-specific TNF-α production and cytotoxicity in a 24-h assay, which was blocked by the soluble TNFRII-human IgG fusion protein (TNFRII:Fc). Blocking TNF in vivo by administering soluble TNFR II fusion protein (TNFRII:Fc) significantly reduced the therapeutic efficacy of PKO/GKO, but not wild-type TE. This study identifies perforin, IFN-γ, and TNF as a critical triad of effector molecules that characterize therapeutic antitumor T cells. These insights could be used to monitor and potentially tune the immune response to cancer vaccines.
Cutting Edge: Dysfunctional CD8+ T Cells Reside in Nonlymphoid Tissues During Chronic Trypanosoma cruzi Infection
Authors: Leavey Jennifer K. , Tarleton Rick L. 
Published: April 2014

Abstract
Chagas disease is caused by persistent Trypanosoma cruzi infection in muscle tissue that ultimately results in chronic inflammation and tissue destruction. It is unclear why T. cruzi is cleared from some tissues but persists in others, despite an active inflammatory response. In this study, we show that the majority of CD8+ T cells present in muscle tissue express memory and effector cell surface markers but have sharply attenuated effector function compared with their splenic counterparts. The dysfunction of CD8+ T cells in the muscle tissue suggests a mechanism by which T. cruzi can persist in that location and cause inflammatory damage.
Cutting Edge: Histamine Inhibits IFN-α Release from Plasmacytoid Dendritic Cells
Authors: Mazzoni Alessandra , Leifer Cynthia A. , Mullen Gregory E. D. , Kennedy Margaret N. , Klinman Dennis M. , Segal David M. 
Published: April 2014

Abstract
Plasmacytoid dendritic cells (DC) are professional APC and a major source of type I IFN following viral infection. We previously showed that histamine alters the cytokine profiles of maturing monocyte-derived DC resulting in a change from Th1 to Th2 in their T cell polarizing function. In this study, we show that human plasmacytoid DC, activated by either CpG oligodeoxynucleotides or viral infection, also respond to histamine through H2 receptors, leading to a marked down-regulation of IFN-α and TNF-α and a moderate switch in their capacity to polarize naive T cells. Our findings provide an explanation for low levels of type I IFN frequently observed in atopic individuals.
Induction of Low Dose Oral Tolerance in Monocyte Chemoattractant Protein-1- and CCR2-Deficient Mice
Authors: Gonnella Patricia A. , Kodali Dhatri , Weiner Howard L. 
Published: April 2014

Abstract
The chemokine monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 have been shown to play an important role in the migration and trafficking of macrophages and Th1 effector cells in experimental autoimmune encephalomyelitis. Also, MCP-1 has been reported to regulate oral tolerance induction by inhibition of Th1 cell-related cytokines and by the ability of Abs to MCP-1 to inhibit oral tolerance. This study demonstrates that neither MCP-1 nor its receptor CCR2 is required for the induction of oral tolerance. Mice deletional for either MCP-1 or CCR2 had suppressed cell-proliferative and Th1 responses following oral administration and immunization with myelin oligodendrocyte glycoprotein (MOG35–55). TGF-β was up-regulated in fed and immunized deletional mice, while IL-4 was absent from deletional mice, but up-regulated in controls. Decreased experimental autoimmune encephalomyelitis severity was found in MOG35–55-fed MCP-1 deletional mice, indicating induction of oral tolerance. These results demonstrate that MCP-1 is not required for induction of oral tolerance and that MCP-1 and CCR2 are essential for up-regulation of IL-4 in tolerized mice.
BATF Transgenic Mice Reveal a Role for Activator Protein-1 in NKT Cell Development
Authors: Williams Kristi L. , Zullo Alfred J. , Kaplan Mark H. , Brutkiewicz Randy R. , Deppmann Christopher D. , Vinson Charles , Taparowsky Elizabeth J. 
Published: April 2014

Abstract
The importance of regulated AP-1 activity during T cell development was assessed using transgenic mice overexpressing BATF, a basic leucine zipper transcription factor and an AP-1 inhibitor. BATF transgenic animals possess normal thymic cellularity and all major T cell subsets, but show impaired thymocyte proliferation in vitro and no induction of IL-2, IL-4, IL-5, IL-10, and IL-13 expression. Since NKT cells are largely responsible for cytokine production in the thymus, this population was examined by detection of the Vα14-Jα281 TCR, flow cytometry of NK1.1+ TCRβ+ cells, and analysis of cytokine production by heat-stable Aglow thymocytes and peripheral NKT cells stimulated in vivo. Results show a severe under-representation of NKT cells in BATF transgenic animals, providing the first evidence that the precise control of AP-1-mediated transcription is critical for the proper emergence of thymus-derived NKT cells in the mouse.
Inhibition of Th2 Differentiation and GATA-3 Expression by BCL-6
Authors: Kusam Saritha , Toney Lisa M. , Sato Hiroshi , Dent Alexander L. 
Published: April 2014

Abstract
The B cell lymphoma (BCL)-6 transcriptional repressor protein is an important regulator of Th2 responses. Mice deficient in BCL-6 develop severe Th2-type inflammation that can develop even in the absence of IL-4 signaling. We have investigated the mechanism for how BCL-6 regulates Th2 cell differentiation and have found that IL-6 signaling can promote dramatically increased levels of Th2 differentiation in BCL-6−/− CD4 T cells compared with wild-type CD4 T cells. IL-6 can induce a low level of Th2 cytokine expression in BCL-6−/−STAT6−/− cells but not in STAT6−/− cells. Since the promoters for Th2 cytokines such as IL-4, IL-5, IL-10, and IL-13 do not contain consensus BCL-6 DNA binding sites, we investigated whether BCL-6 might regulate the GATA-3 transcription factor that activates the expression of multiple Th2 cytokines. Consistent with the idea that BCL-6 represses GATA-3 expression, we found that GATA-3 levels are up-regulated in BCL-6−/−STAT6−/− CD4 T cells compared with STAT6−/− CD4 T cells. Retrovirus-mediated expression of BCL-6 in BCL-6−/−STAT6−/− T cells as well as developing wild-type Th2 cells leads to a potent repression of IL-4 and IL-10 secretion. Retrovirus-mediated expression of BCL-6 in both BCL-6−/−STAT6−/− and wild-type T cells also leads to a significant decrease in GATA-3 protein levels. Surprisingly, BCL-6 does not appear to regulate GATA-3 mRNA levels and thus BCL-6 appears to regulate GATA-3 expression at a posttranscriptional level. Regulation of GATA-3 protein levels is likely a key mechanism for how BCL-6 regulates Th2 cytokine expression and Th2 differentiation independently of STAT6. These data also point to a novel regulatory mechanism for BCL-6 separate from transcriptional repression.
Immediate Early Effector Functions of Virus-Specific CD8+CCR7+ Memory Cells in Humans Defined by HLA and CC Chemokine Ligand 19 Tetramers
Authors: Ravkov Eugene V. , Myrick Christy M. , Altman John D. 
Published: April 2014

Abstract
Memory T cells exhibit a high degree of heterogeneity in terms of their phenotype and functional characteristics. It has been proposed that the CCR7 chemokine receptor divides memory T cell populations into central memory T cells and effector memory T cells with distinct functions in secondary immune responses. We were interested whether this hypothesis holds true in experiments performed on Ag-specific CD8+ T cells. To identify CCR7+ cells, we engineered a fluorescent ligand for CCR7; results with the new CC chemokine ligand 19 chemotetramer were verified by staining with a CCR7 mAb. Staining with the CC chemokine ligand 19 chemotetramer reveals two subsets within CCR7+ cells: a CCR7int population containing memory cells and a CCR7high population containing naive T cells. Phenotypic analysis of MHC class I/peptide tetramer-positive cells revealed that HLA-A2-restricted CMV-specific CD8 T cells exhibit the lowest percentage of CCR7+ cells (0.5–5%), while HLA-A2-restricted flu- and HLA-B8-restricted EBV-specific CD8 T cells showed the highest (45–70%). Intracellular staining of unstimulated cells revealed that both CCR7int- and CCR7−-specific CD8 T cells exhibit a detectable level of perforin. Both CCR7int and CCR7− Ag-specific CD8+ T cells produced IFN-γ and TNF-α following short-term peptide stimulation. Therefore, our finding that CCR7+CD8+ T cells are able to exert immediate effector functions requires a substantial revision to the central and effector memory hypothesis.