bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selection of T cells reactive against autologous B lymphoblastoid cells during chronic rheumatoid arthritis.
Authors: David-Ameline J , Lim A , Davodeau F , Peyrat M A , Berthelot J M , Semana G , Pannetier C , Gaschet J , Vie H , Even J , Bonneville M 
Published: December 2022

Abstract
The repertoire and Ag specificity of T cells infiltrating inflamed joints from a chronic rheumatoid arthritis (RA) patient were studied in detail. Repertoire analysis demonstrated a reduced clonality of joint-infiltrating lymphocytes (JIL) as compared with patient's PBL, which was presumably due to an intra-articular expansion of T cell clones with recurrent TCR features. Strikingly, a large fraction of these JIL T cell clones, which were predominantly CD8+, proliferated in vitro when exposed to autologous B lymphoblastoid cells (BLC), unlike randomly chosen PBL clones derived from the same patient. This proliferative response was HLA-restricted, which confirmed a classical TCR-mediated recognition of BLC and was not observed against autologous PHA blasts, suggesting recognition of either EBV or B cell-specific Ags. Finally, a preliminary analysis of synovial lymphocytes derived from another chronic RA patient demonstrated a similar enrichment for T cells reactive against autologous BLC within JILs as compared with patient's PBLs. Taken together, these results, which suggest frequent expansions of autologous BLC-reactive T cells within inflamed joints of chronic RA patients, provide a basis for future studies evaluating the fine specificity and pathogenicity of these lymphocytes.
CD11b+CD28-CD4+ human T cells: activation requirements and association with HLA-DR alleles.
Authors: Chapman A , Stewart S J , Nepom G T , Green W F , Crowe D , Thomas J W , Miller G G 
Published: December 2022

Abstract
Engagement of CD28 induces a major costimulatory pathway required by many CD4+ T cells in addition to activation via the TCR. In the absence of signals provided by CD28, ligation of the TCR alone can induce anergy or apoptosis in CD28+ cells. However, we report here characterization of a distinct subset of CD4+ T cells that are CD28-. Three autoreactive CD4+ human T cell clones that could be activated to produce IL-2 and proliferate by anti-CD3 alone were found to lack expression of CD28. CD28- clones that were activated with anti-CD3 alone were not anergic to restimulation via CD3. The presence of CD28-CD4+ T cells was verified in peripheral blood, and their frequency ranged from 0% to &gt;22% of CD4+ T cells in different individuals. The percentage of CD28-CD4+ T cells in the peripheral blood of 57 individuals was significantly correlated with specific class II MHC alleles. Persons with HLA-DRB1*0401 and DR1 alleles had significantly higher numbers of CD28- T cells, while individuals with HLA-DR2(15) had significantly fewer CD28-CD4+ T cells than the mean. Like the CD28- clones, CD28-CD4+ T cells isolated from peripheral blood proliferated upon CD3 cross-linking in the absence of costimulation. The finding that CD28-CD4+ T cells resist induction of anergy following engagement of the TCR in the absence of conventional costimulation demonstrates one mechanism by which autoreactive T cells can escape processes that censor self-reactivity. The MHC associations observed suggest a relationship with autoimmunity and loss of self-tolerance.
Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation.
Authors: Cho S S , Bacon C M , Sudarshan C , Rees R C , Finbloom D , Pine R , O'Shea J J 
Published: December 2022

Abstract
The immunoregulatory cytokine IL-12 plays a central role in cell-mediated immune responses through its effects on NK cells and T lymphocytes. While IL-12 is known to share some functions with other cytokines, such as IFN-alpha, it also maintains distinct roles, such as its ability to induce Th1 differentiation. The molecular basis for these unique and overlapping functions is not well understood. IL-12 has previously been shown to induce tyrosine phosphorylation and DNA-binding of STAT3 and STAT4, members of the signal transducers and activators of transcription (STAT) family. Because STAT4 has only been shown to be activated in response to IL-12, this specificity has been suggested to be a basis for the unique actions of IL-12. In this study, we demonstrated that STAT4 activation by IL-12 is not unique; IL-12 and IFN-alpha, but not IFN-gamma, induced tyrosine phosphorylation and DNA binding of STAT4. Since tyrosine and serine phosphorylation of STAT1 have previously been shown to be important in IFN-alpha-mediated signaling, we also investigated IL-12- and IFN-alpha-induced serine phosphorylation of STAT4. We demonstrated that both cytokines induced serine phosphorylation. This modification was not required for DNA binding, but may be important in STAT-mediated transcription. Thus, STAT4 activation was not IL-12 specific, and IL-12 and IFN-alpha activated STAT4 through both tyrosine and serine phosphorylation. These findings have significant implications for understanding the role of STAT4 in mediating biologic functions; specifically, the data argue that the unique effects of IL-12 cannot be solely explained by STAT4 activation.
Contribution of the CD28 molecule to allergic and irritant-induced skin reactions in CD28 -/- mice.
Authors: Kondo S , Kooshesh F , Wang B , Fujisawa H , Sauder D N 
Published: December 2022

Abstract
The CD28 molecule is thought to be essential for the costimulatory signals and is required for mitogenic activation of T cells. The aim of this study was to evaluate the contribution of CD28 in contact hypersensitivity using CD28 gene-targeted (CD28 -/-) mutant mice. Contact hypersensitivity to dinitrofluorobenzene and oxazolone was significantly decreased in CD28 -/- mice compared with that in normal (C57BL/6) mice. Significant increases in IL-2 mRNA were detected in the skin after dinitrofluorobenzene challenge in normal mice, while this response was blunted in CD28 -/- mice. In addition, responses to irritant chemicals (croton oil and phenol) were also impaired in CD28 -/- mice. IL-2, IFN-gamma, and TNF-alpha mRNA levels were lower in CD28 -/- mouse skin treated with phenol. T cells from CD28 -/- mice did not bind to epidermal cells derived from normal mice, while cocultivation of T cells with epidermal cells from normal mice demonstrated a significant binding. These results indicate that the CD28 molecule is required not only for optimal induction of allergic contact dermatitis, but also for the development of irritant-induced skin inflammation. The expression of B7-1 and B7-2 molecules on epidermal cells was induced by an allergen treatment in normal and CD28 -/- mice, whereas only B7-2 was induced after irritant treatment. Lack of CD28 signaling may influence cutaneous inflammation by modulating skin cytokine profiles, possibly due to the decreased contact of T cells with other cell populations expressing ligands for CD28. In addition, the results of this study suggest that allergic contact dermatitis and irritant dermatitis have overlapping pathophysiologic mechanisms, but subtle differences exist.
DM-mediated release of a naturally occurring invariant chain degradation intermediate from MHC class II molecules.
Authors: Stebbins C C , Peterson M E , Suh W M , Sant A J 
Published: December 2022

Abstract
The nonpolymorphic, nonclassical class II molecule DM has been shown to be important in the processing and presentation of antigenic epitopes by MHC class II molecules. The dependence of class II molecules on the coexpression of DM varies with the particular allele or epitope studied. In an effort to resolve disparities that exist for some alleles of class II in their requirements for DM, we have constructed a species-matched murine transfection model with which we can test both the functional and biochemical consequences of DM expression for different alleles of murine class II. When we evaluated the ability of class II molecules to form SDS-stable dimer and release CLIP, we find that while I-A(d) requires DM for the formation of SDS-stable dimers and the release of CLIP, I-A(k) is capable of both SDS-stable dimer formation and CLIP release in the absence of DM. Despite the apparent differences in the biochemical consequences of DM expression for I-A(d) and I-A(k), we find that Ag presentation by both alleles can be enhanced by the expression of DM. Interestingly, we find that DM can facilitate the removal of a natural intermediate in Ii processing (p12). The ability of DM to catalyze the dissociation of p12 and possibly larger Ii fragments from class II in vivo offers a possible mechanism to account for the observed DM enhancement of Ag presentation for alleles that have a low affinity for CLIP. Our findings indicate that DM may function in multiple compartments and on multiple class II/Ii substrates.
Humoral immune responses in L-selectin-deficient mice.
Authors: Steeber D A , Green N E , Sato S , Tedder T F 
Published: December 2022

Abstract
L-selectin regulates lymphocyte migration by mediating lymphocyte attachment to high endothelial venules of peripheral lymph nodes (PLN). L-selectin-deficient mice display a 70 to 90% reduction in the number of lymphocytes within PLNs and a 30 to 55% increase in spleen cellularity. The altered distribution of lymphocyte subpopulations in L-selectin-deficient mice resulted in significantly elevated serum IgM and IgG1 levels and augmented humoral immune responses to T cell-independent and T cell-dependent Ags following i.p. immunization. By contrast, s.c. immunization of L-selectin-deficient mice with a T cell-dependent Ag resulted in serum IgM responses that were 40% lower when compared with wild-type littermates on day 7, while primary IgG responses were essentially absent. Most serum Ig responses were normal by day 14 and secondary responses were higher in L-selectin-deficient mice. Although lymphocytes from L-selectin-deficient mice were unable to enter Ag-stimulated lymph nodes through high endothelial venules, the cellularity of draining lymph nodes increased significantly following immunization. Germinal centers developed rapidly following immunization, although PLNs of L-selectin-deficient mice contained few follicles. Germinal centers within PLNs and the spleen were also consistently much larger and more well defined in L-selectin-deficient mice when compared with wild-type littermates. These results confirm that lymphocyte migration plays an important role in the initiation of humoral responses and demonstrate complementary and overlapping roles for the spleen and other peripheral lymphoid tissues in the generation of immune responses.
Multiple interactions of IgG with its core oligosaccharide can modulate recognition by complement and human Fc gamma receptor I and influence the synthesis of its oligosaccharide chains.
Authors: Lund J , Takahashi N , Pound J D , Goodall M , Jefferis R 
Published: December 2022

Abstract
Glycosylation at Asn297 within the CH2 domains of IgG is important for recognition by the effector ligands Fc gammaR and C. Protein engineering has been used to replace amino acid residues within the extensive oligosaccharide interaction site that contact the core hexasaccharide (GlcNAc2Man3GlcNAc). Replacement of residues Phe241, Val264, or Asp265, in particular, results in reduced recognition of human chimeric anti-nitroiodophenacetyl IgG3 produced in Chinese hamster ovary cells, by guinea pig C and human C1q. Replacement of residues Val264 or Asp265, in particular, results in reduced superoxide production triggered through human Fc gammaRI expressed on U937 cells. These results suggest that noncovalent interactions of multiple amino acid residues of IgG with oligosaccharide residues that include the primary and secondary GlcNAc are necessary for optimal recognition of IgG by human Fc gammaRI and C1q. Replacement of residues 241, 243, 264, 265, or 301 with alanine in each case resulted in increased galactosylation and sialylation relative to the wild-type oligosaccharide chains. In particular, for the mutant FA243 there was much increased sialylation of its oligosaccharide chains (73%) relative to the wild-type (4%). Thus, even single residue replacements within the oligosaccharide interaction site of the C region can influence galactosylation and sialylation of its oligosaccharide chains. These data suggest a protein engineering route to the production of more homogeneously glycosylated IgG molecules with or without compromised biologic activities.
TCR alpha-chain usage can determine antigen-selected TCR beta-chain repertoire diversity.
Authors: Turner S J , Cose S C , Carbone F R 
Published: December 2022

Abstract
There is considerable variation in the TCR repertoire diversity selected by different peptide Ags. Certain responses show limited V region bias with minimal restrictions in the remainder of the sequence while others can be dominated by a single TCR clonotype repeatedly isolated from different individuals. CTL specific for a Kb-restricted determinant from the herpes simplex virus glycoprotein B (gB) preferentially express a dominant TCRBV10 beta-chain subset with extensive conservation located at the V-D junction. However, unlike some biased responses, no single beta-chain V-D-J combination appears to dominate these CTL. Different animals respond with a large array of unique or "private" beta-chain sequences with little J region preference. Here we examine the contribution of the TCR alpha-chain to the gB-specific CTL diversity. The TCR alpha-chains from different TCRBV10-positive gB-specific CTL clones were found to exhibit extensive sequence variation. However, when T cells were forced to use a single alpha-chain in TCR alpha-chain transgenic mice, gB-specific CTL showed limited variation in their beta-chain selection. These T cells retained the TCRBV10 bias but were now dominated by a single beta-chain sequence that could be repeatedly isolated from different transgenic animals. This "public" TCR consisted of the transgenic alpha-chain and a common TCRBV10D2J2S6 beta-chain. These results suggest that preferential use of one TCR subunit can restrict the level of diversity in the other chain due to interchain interactions involving J-derived sequences.
Humoral immunity and regulation of intrapulmonary growth of Legionella pneumophila in the immunocompetent host.
Authors: Brieland J K , Heath L A , Huffnagle G B , Remick D G , McClain M S , Hurley M C , Kunkel R K , Fantone J C , Engleberg C 
Published: December 2022

Abstract
The potential role of humoral immunity in regulating intrapulmonary growth of Legionella pneumophila in the immunocompetent host was investigated using a murine model of Legionnaires' disease. Intratracheal inoculation of A/J mice with a virulent strain of L. pneumophila (10(6) bacteria per mouse) resulted in the recruitment of B lymphocytes into the lung and the development of anti-L. pneumophila Ab. Opsonization of L. pneumophila in vitro with anti-L. pneumophila-specific mAb resulted in a significant decrease in intrapulmonary growth of the bacteria at 24 to 72 h postinfection. Transmission electron microscopic analysis of lung tissue from L. pneumophila- infected mice demonstrated that while there was no significant difference between phagocytosis of the unopsonized and opsonized L. pneumophila by alveolar macrophages at 24 h postinfection, phagocytosis of opsonized bacteria by alveolar mononuclear phagocytic cells was significantly enhanced at 48 h postinfection. Depletion of A/J mice of complement before intratracheal inoculation of opsonized L. pneumophila (10(6) bacteria per mouse) did not significantly alter intrapulmonary growth of L. pneumophila. These results suggest that anti-L. pneumophila Ab, produced during replicative L. pneumophila lung infections, may regulate intrapulmonary growth of L. pneumophila in the immunocompetent host by decreasing the viability of extracellular L. pneumophila and by enhancing phagocytosis of the bacteria by alveolar mononuclear phagocytic cells by a complement-independent mechanism.
Corynebacterium parvum- and Mycobacterium bovis bacillus Calmette-Guerin-induced granuloma formation is inhibited in TNF receptor I (TNF-RI) knockout mice and by treatment with soluble TNF-RI.
Authors: Senaldi G , Yin S , Shaklee C L , Piguet P F , Mak T W , Ulich T R 
Published: December 2022

Abstract
The aim of this study was to examine the role of TNF receptor I (TNF-RI) in the pathogenesis of heat-killed Corynebacterium parvum- and live bacillus Calmette-Guerin (BCG)-induced granulomas. Granuloma formation was analyzed in TNF-RI knockout mice and after treatment with soluble TNF-RI (sTNF-RI). TNF-RI knockout mice injected with C. parvum or BCG developed fewer and smaller granulomas than wild-type control mice. Mice treated with sTNF-RI from days 7 to 13 after injection of C. parvum or BCG developed fewer and smaller granulomas than saline-treated control mice. Established granulomas regressed in rats treated with sTNF-RI from days 10 to 13 after injection of C. parvum. In conclusion, TNF signaling via TNF-RI contributes to the pathogenesis of C. parvum- and BCG-induced granulomas. sTNF-RI inhibits the development of granulomas and can cause the regression of established granulomas.
Shared epitopes for HLA-A3-restricted melanoma-reactive human CTL include a naturally processed epitope from Pmel-17/gp100.
Authors: Skipper J C , Kittlesen D J , Hendrickson R C , Deacon D D , Harthun N L , Wagner S N , Hunt D F , Engelhard V H , Slingluff C L 
Published: December 2022

Abstract
Human CD8+ CTL recognize peptides bound to class I MHC molecules on the surface of melanoma cells. Several peptides derived from melanocyte lineage-specific proteins have been identified as epitopes for HLA-A2 restricted melanoma-reactive CTL. Because less than half of melanoma patients express HLA-A2, it is important to identify CTL epitopes restricted by other common MHC molecules including HLA-A1 and -A3. We have generated HLA-A3-restricted human CTL that recognize one or more shared melanoma Ags. All of the melanomas recognized by one of these CTL lines express Pmel-17/gp100, and those that fail to express this Ag are not lysed. This CTL line also specifically recognizes the lymphoblastoid line C1R-A3 following infection with a recombinant vaccinia encoding the melanocyte lineage-specific protein Pmel-17/gp100. Thus, at least one Pmel-17/ gp100 peptide is an epitope for this CTL line. We have identified ALLAVGATK (Pmel-17/gp100 residues 17-25) as an epitope for this CTL line and have shown that it is naturally processed and presented by HLA-A3 on melanoma cells. A second HLA-A3-restricted melanoma-reactive CTL line recognizes at least one additional shared epitope. These findings suggest that cellular immune responses directed against multiple shared melanoma epitopes exist in the 20 to 25% of melanoma patients who express HLA-A3. In addition, immunotherapy directed against Pmel-17/gp100 and other shared melanoma Ags may be useful in a large subset of these patients.
Overexpression of RANTES using a recombinant adenovirus vector induces the tissue-directed recruitment of monocytes to the lung.
Authors: Braciak T A , Bacon K , Xing Z , Torry D J , Graham F L , Schall T J , Richards C D , Croitoru K , Gauldie J 
Published: December 2022

Abstract
RANTES (regulated on activation, normal T cell expressed and secreted) is a member of the C-C superfamily of chemokines and is reported to function as a potent chemoattractant for monocytes, eosinophils, and a subpopulation of CD4+ T cells. Using a recombinant human type 5 adenovirus containing the murine RANTES cDNA (Ad5E3 mRANTES), which is capable of expressing biologically active cytokine upon infection, we initiated a study to characterize the biologic functions of RANTES cytokine in vivo. Intratracheal administration of Ad5E3 mRANTES targeted transient RANTES expression to the bronchial epithelium of the lung in Sprague-Dawley rats. Bronchoalveolar lavage fluids (BAL) collected at 24 h had increased chemotactic activity vs controls as measured in a murine CD4+ T cell Boyden chamber microchemotaxis assay. There was a dramatic increase in the number of cells (macrophage, monocytes, and neutrophils) recovered from BAL samples taken from Ad5E3 mRANTES-treated animals at 24 h, with a &gt;50-fold increase in monocytes, indicating a proinflammatory effect for this cytokine in vivo. This effect on monocytes was transient, decreasing by 7 days, with evidence of increased eosinophils and lymphocytes at this time. Histologic examination of lung sections at 24 h revealed greatly increased numbers of mononuclear cells, primarily monocytes, within the lungs of Ad5E3 mRANTES-treated animals, with increased extravasation of monocytes around blood vessels, indicating an ongoing process of peripheral blood monocyte recruitment. This study provides further evidence for RANTES to be a monocyte chemoattractant in vivo.
The role of protein tyrosine phosphatase SHP-1 in the regulation of IFN-gamma signaling in neural cells.
Authors: Massa P T , Wu C 
Published: December 2022

Abstract
The role for protein tyrosine phosphatase SHP-1 in controlling signal transduction by IFN-gamma in astrocytes was studied. IFN-gamma induced the gamma-activated factor (GAF) within 30 min and GAF subsequently declined by 8 h after treatment. However, treatment with IFN-gamma in the presence of protein tyrosine phosphatase inhibitor vanadate blocked the decrease in GAF activity. The increased stability of GAF in vanadate-treated cultures was similarly observed in astrocytes of motheaten mice, which specifically lack the protein tyrosine phosphatase SHP-1. Prolongation of GAF activity coincided with increased expression of the IFN-inducible transcription factor, IFN-regulatory factor-1 (IRF-1). Increased IRF-1 was coincident with increased expression of MHC class I molecules in astrocytes in accordance with the activity of IRF-1 in the promoter region. These data implicate an important role for protein tyrosine phosphatases, including SHP-1, in the regulation of IFN-gamma-signaling and IFN-gamma-inducible genes in neural cells.
Extrathymic differentiation of resident T cells in the joints of mice with collagen-induced arthritis.
Authors: Arai K , Yamamura S , Hanyu T , Takahashi H E , Umezu H , Watanabe H , Abo T 
Published: December 2022

Abstract
Murine collagen-induced arthritis (CIA) is known as a T cell-mediated autoimmune disease, although autoantibodies are also suspected to be associated with the onset of the disease. To determine the origin of such T cells in the joints of mice with CIA, their phenotypic properties as well as those of T cells in other immune organs were examined in DBA/1 mice. Since a significant number of mononuclear cells (MNC) was also yielded by the joints of normal DBA/1 mice, the properties of these T cells were examined in parallel. When CIA was induced by an intradermal injection of type II collagen at the base of the tail, the numbers of MNC yielded by the regional lymph nodes and the foot joints were doubled. Interestingly, regardless of the onset of CIA, the joints were always comprised of unique T cell populations, including IL-2(R)alpha- beta+ T cells, gammadelta T cells, CD8alpha+ beta- cells, and CD44+ L-selectin- cells. All these properties coincide with those of extrathymic T cells in liver and intestine. In the case of gammadelta T cells in joints, Vgamma and Vdelta usages were unique and different from those in the other organs. More importantly, Vgamma and Vdelta usages in gammadelta T cells in the joints of normal mice and in those of mice with CIA were essentially the same. Taken together with the expression of recombination-activating gene-1 and -2 mRNAs by MNC in mice with CIA, these findings raise the possibility that the joints have their own resident T cells that are extrathymically generated in situ.