bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of responsiveness in superantigen-induced anergic T cells. Role of ligand density and costimulatory signals.
Authors: Heeg K , Wagner H 
Published: December 2022

Abstract
The bacterial superantigen staphylococcal enterotoxin B (SEB) induces in vivo a state of anergy defined by the inability of V beta 8+ CD4+ T cells to produce IL-2 upon restimulation in vitro. However, restimulation in vivo triggers a burst of acutely released lymphokines including IL-2 and TNF, paralleled by up-regulation of lymphokine-specific mRNA. Since anergy as defined in vitro appears not to operate in vivo, we analyzed parameters able to induce responsiveness in anergic T cells. We show here that in vitro stimulation of anergic T cells with competent Ag-presenting cells induces responsiveness, provided the APC (activated B cells or dendritic cells) present high concentrations of SEB. Crosslinking of CD28 molecules on anergic T cells could substitute the requirement for competent APC. Quantitation of TCR threshold by determining the SEB concentrations able to trigger half-maximal T cell responses revealed that anergic and normal T cells exhibited the same TCR threshold for the expression of functional IL-2 receptors (IL-2R), yet the TCR threshold for induction of IL-2 production was 10- to 100-fold elevated in anergic T cells. TCR threshold for normal and anergic T cells was further dependent on the type of APC, i.e., costimulus-competent APC required 100-fold less SEB. The results indicate that extrinsic factors such as ligand concentration and costimulus competence of APC can overcome the heightened TCR threshold of anergic T cells, thus reverting anergy into responsiveness.
Human DNA-activated protein kinase (DNA-PK) is homologous to phosphatidylinositol kinases.
Authors: Poltoratsky V P , Shi X , York J D , Lieber M R , Carter T H 
Published: December 2022

Abstract
DNA-activated protein kinase (DNA-PK) is a serine/threonine protein kinase that interacts with a DNA end-binding heterodimeric protein, Ku, and is activated by double-stranded DNA. Genomic clones that contain the DNA-PK gene complement the murine scid defect, indicating that DNA-PK affects double-strand break repair and V(D)J recombination. Here we describe the cDNA sequence of the region that corresponds to about 100 kDa of C-terminal sequence of this large (&gt; p350 kDa) protein. This region contains a kinase domain that has strong homology to phosphatidylinositol kinases.
Enhancement of VLA integrin receptor function on thymocytes by cAMP is dependent on the maturation stage of the thymocytes.
Authors: Halvorson M J , Coligan J E 
Published: December 2022

Abstract
A class of adhesion molecules, the VLA integrins, are expressed on thymocytes and have been shown to affect immature thymocyte differentiation in vitro. This study examines the ability of cAMP to regulate VLA receptor function in thymocytes. Pharmacologic agents that raise intracellular cAMP enhanced the binding of immature CD4- CD8- and CD4+ CD8+ thymocytes to fibronectin while having no effect on the binding of the more mature JIId- thymocytes. PGE2, a hormone produced by thymic epithelial cells and known to raise intracellular cAMP levels in thymocytes, also increased the binding of immature thymocytes to fibronectin. In contrast, activation of protein kinase C via PMA enhanced the binding of all three thymocyte subsets. The cAMP-induced binding was blocked by mAbs to the VLA integrin chains alpha 4 and alpha 5 and by the protein kinase A (PKA) inhibitor, (Rp)-cAMPS, indicating that activation of PKA enhances VLA-4 and VLA-5 receptor function. Activation of PKA was induced in all three thymocyte subsets following addition of cAMPa or forskolin, indicating that the inability of cAMP to enhance the binding of JIId- thymocytes was not due to an inability to activate PKA. Thus, cAMP enhances integrin function in thymocytes in a maturation stage-specific manner.
Early activation signal transduction pathways of Th1 and Th2 cell clones stimulated with anti-CD3. Roles of protein tyrosine kinases in the signal for IL-2 and IL-4 production.
Authors: Tamura T , Nakano H , Nagase H , Morokata T , Igarashi O , Oshimi Y , Miyazaki S , Nariuchi H 
Published: December 2022

Abstract
In the present experiments, TCR-CD3-associated early activation signal transduction pathways were examined in Th1 and Th2 clones by the stimulation with soluble monovalent anti-CD3 which resulted in efficient production of IL-2 and IL-4 in Th1 and Th2 cells, respectively. Although protein tyrosine kinases such as Fyn and ZAP-70 were activated in Th1 clones shortly after stimulation, these kinases in Th2 clones were not activated; but, their activity in resting conditions was shown to be decreased by the stimulation. In accordance with these findings, neither phospholipase C-gamma 1 activation nor phosphatidyl inositol-4,5-bisphosphate breakdown was induced in Th2 clones, in contrast to positive responses in Th1 clones. The oscillation of intracellular free Ca2+ concentration ([Ca2+]i) was a common signal for the activation of both Th1 and Th2 clones; however, the [Ca2+]i elevation in Th1 clones was herbimycin A sensitive, whereas that in Th2 was clone resistant, suggesting that the mechanism of the [Ca2+]i elevation in Th2 cells is different from that in Th1 cells in terms of the participation of protein tyrosine kinases. The anti-CD3 stimulation did not cause Lck activation in either the Th1 or Th2 clone, although remarkable activation was induced in both clones following anti-CD4 stimulation, indicating that Lck activation was not required for either IL-2 or IL-4 production of Th cells. Taken together, these results indicate that Th1 and Th2 cells are different from each other in early activation signal transduction pathways, especially in the role of protein tyrosine kinases.
Induction of cell-mediated immune responses to human immunodeficiency virus type 1 Gag protein by using Listeria monocytogenes as a live vaccine vector.
Authors: Frankel F R , Hegde S , Lieberman J , Paterson Y 
Published: December 2022

Abstract
Cytolytic T cells, acting through cytokines or by direct lysis of infected target cells, have been shown to play a significant role in the control of viral infections and may be responsible for the prolonged asymptomatic phase following infection by HIV. Accordingly, methods that can generate strong cell-mediated immune responses may be useful in the development of prophylactic and therapeutic vaccines against HIV. Listeria monocytogenes is a Gram-positive intracellular microorganism that elicits strong cell-mediated immune responses against its own secreted proteins following infection. In this study we have modified the chromosome of L. monocytogenes so that it stably expresses and secretes the p55 HIV gag gene product and examined the cell-mediated immune response of BALB/c mice to infection with this recombinant organism. Infected animals were found to mount a specific, strong, long-lasting CD8+ cytolytic T cell response against a predominant epitope contained within the p24 fragment of the HIV Gag protein. This epitope previously has been shown to be recognized by CTLs obtained from some HIV-infected humans. Our results suggest that chromosomally modified strains of L. monocytogenes may provide valuable vaccine vectors for use against HIV.
Identification and characterization of the complement C5a anaphylatoxin receptor on human astrocytes.
Authors: Gasque P , Chan P , Fontaine M , Ischenko A , Lamacz M , Götze O , Morgan B P 
Published: December 2022

Abstract
The C fragment C5a exerts its important physiologic and pathologic effects through interaction with a specific C5a receptor (C5aR) which is highly expressed on polymorphonuclear leukocytes and some other leukocytes. The presence of this receptor on epithelia and endothelia has recently been documented, raising the possibility that these other cells might also respond to locally generated C5a. C has been implicated in several brain disorders, notably demyelination and neurodegeneration, and cells within brain can synthesize a complete C system. It is thus of interest to examine the mechanisms by which C damages or activates brain cells. To this end we have examined the expression on human fetal astrocytes and astrocyte-derived cell lines of receptors for C fragments. We here report that human astrocytes and cell lines express a receptor for C5a (48 to 72 x 10(3) copies/cell), which is indistinguishable at the protein or mRNA level from that in leukocytes. The astrocyte C5aR was recognized by five different specific Abs, which revealed by Western blotting a protein of 40 to 45 kDa in primary human astrocytes and astrocyte cell lines. Expression was confirmed by RT-PCR using multiple primers. Neither inflammatory cytokines nor PMA caused up-regulation of the receptor on astrocytes. The receptor was functional in that addition of C5a (1 nM to 100 nM) or, at high doses (100 nM), C5adesArg, triggered a calcium transient in astrocytes. We propose that C5aR expression on astrocytes plays an important role in control of inflammation in brain and may be a central component of C-mediated brain injury.
Evidence for superantigen involvement in cardiovascular injury due to Kawasaki syndrome.
Authors: Leung D Y , Giorno R C , Kazemi L V , Flynn P A , Busse J B 
Published: December 2022

Abstract
Kawasaki syndrome (KS), the major cause of acquired heart disease in children, is an acute multisystem vasculitis frequently associated with the development of myocarditis and coronary artery abnormalities. Despite the widely held belief that KS is an infectious disease, its etiology has remained elusive. Recently, we and others have reported the selective expansion of V beta 2+ T cells in the peripheral blood of most patients in the acute, but not in the convalescent, phase of KS. These data were consistent with the concept that this illness is triggered by a bacterial superantigen. We report here that a patient who died of acute KS had selective expansion of V beta 2+ T cells in her myocardium and coronary artery. Sequence analysis of TCR beta-chain genes of V beta 2+ T cells from the myocardium showed extensive junctional region diversity. These observations, along with the demonstration of V beta 2 expansion in both the CD4+ and CD8+ T cell subsets, support the concept that the activation of infiltrating V beta 2+ T cells are involved in the cardiovascular damage associated with KS.
T cell epitope mapping of ragweed pollen allergen Ambrosia artemisiifolia (Amb a 5) and Ambrosia trifida (Amb t 5) and the role of free sulfhydryl groups in T cell recognition.
Authors: Zhu X , Greenstein J L , Rogers B L , Kuo M C 
Published: December 2022

Abstract
Ambrosia artemisiifolia (Amb a 5; Ra5S) and Ambrosia trifida (Amb t 5; Ra5G) are homologous allergens purified from short and giant ragweed pollen, respectively. Allergic human sera and hyperimmunized animal antisera directed against Amb a 5 or Amb t 5 show a high degree of species specificity, with little or no cross-reactivity between these two allergens, suggesting that the major Ab binding epitopes of Amb a 5 and Amb t 5 are distinct. Overlapping synthetic peptides derived from the allergen sequences were used to investigate the specificity of T cell responses in four strains of mice, BALB/c (H-2d), CBA (H-2k), C57BL/6 (H-2b), and A/J (H-2a). All four strains of mice responded to purified Amb a 5 and Amb t 5. Cross-reactivity was found at the T cell level between Amb a 5 and Amb t 5 in T cells from BALB/c, A/J, and CBA mice, but not in T cells from C57BL/6 mice. A T cell epitope from Amb a 5, residues 27-36 (PWQVVCYESS), was mapped using T cell hybridomas from BALB/c mice. A T cell epitope in Amb t 5 was mapped in the same strain to residues 24-34 (KYCVCYDSKAI). Disulfide bonds in Amb a 5 and Amb t 5 were found to be involved in T cell reactivity. Conversion of disulfide bridges into free sulfhydryl (SH) forms was required for the response of T cell hybridomas to peptide t5 (residues 27-40) from Amb t 5. Reduction of peptide a4 (residues 21-37) from Amb a 5 was essential for inducing the cross-reactivity observed with Amb t 5-specific T cell hybridomas. It is concluded that free sulfhydryl groups play a major role in the T cell recognition of cross-reactivity T cell epitopes within these related allergens.
CTL in mice immunized with human mucin 1 are MHC-restricted.
Authors: Apostolopoulos V , Loveland B E , Pietersz G A , McKenzie I F 
Published: December 2022

Abstract
CTLs that recognize tumor Ags have been described in mice and humans, particularly for melanoma. These CTLs are CD8+, which is MHC-restricted. In contrast, in human carcinomas of the breast, pancreas, or ovary, and in multiple myeloma, CD8+ CTLs have been described that lyse targets expressing human MUC1 in a non-MHC-restricted manner. On the basis of these observations, we immunized mice with conjugates of mannan-human fusion protein, human mucin 1 (MUC1), which produced CD8+ CTLs. In contrast to the human anti-MUC1 CTLs found in cancer patients, the murine anti-MUC1 CTLs were clearly MHC-restricted, e.g., in inbred mice of the H-2-b, d, k, s, or z haplotypes; the H-2 restriction was also confirmed in H-2 congenic strains. Tests of H-2 recombinant strains demonstrated that MUC1 peptides were able to associate with D or K class I molecules of the b, d, or k haplotypes. Mice lacking MHC-class I molecules made weak CTL responses that were H-2Db-restricted, and in the class I H-2Kbm1 mutant strain, CTL restriction was also shown. Finally, cold target inhibition studies demonstrated that Kb and Db are recognized similarly, but Kk is less well recognized. Thus, anti-MUC1 CTLs induced by immunization of mice are different from those obtained from patients. The immunization of cancer patients with MUC1 peptides is now undergoing clinical trials and it will be of interest to observe whether the CTLs induced are HLA-restricted, not restricted, or whether both types of CTLs are produced.
B7/CD28-dependent and -independent induction of CD40 ligand expression.
Authors: Ding L , Green J M , Thompson C B , Shevach E M 
Published: December 2022

Abstract
The induction of a T cell-dependent Ab response is mediated by the interaction of the T cell activation Ag, CD40 ligand (CD40L), with CD40. Since this interaction is independent of Ag, coreceptors such as CD4, and MHC molecules, the expression of the CD40L must be strictly regulated or B cell-mediated autoimmunity may be produced. In this study, we examined the requirements for costimulatory signals for induction of CD40L expression in vitro and in vivo on CD4+ T cells from normal and CD28-deficient mice following stimulation with anti-CD3, Con A, or specific peptide Ag. Expression of B7-1 was both necessary and sufficient for induction of the CD40L on normal CD4+ T cells when L cell transfectants were used as APCs. When normal accessory cell populations were used, only partial inhibition of induction of the CD40L was observed with reagents that inhibit B7/CD28 interactions. Furthermore, the CD40L could be induced on CD4+ T cells from CD28-deficient mice. Thus, non-B7/CD28 cellular interactions can also mediate the costimulatory signals needed for induction of CD40L expression.
Dissociated expression of granulocyte-macrophage CSF and IL-3 in short-term T cell clones from normal mice.
Authors: Fitzpatrick D R , Kelso A 
Published: December 2022

Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3 are generally thought to be produced in a coordinated fashion by all activated T cells. We have examined this premise using quantitative kinetic analyses of the expression of GM-CSF and IL-3 in clonal cultures of mouse T cells for the first two weeks following in vitro stimulation with solid-phase TCR- and accessory molecule-specific mAbs. We demonstrate that 1) differential secretion of GM-CSF and IL-3 is a feature of high proportions of CD8+ and CD4+ T cell clones, for extended periods of time following activation; 2) multiple patterns of expression of these two cytokines can occur, including equivalent, GM-CSF-biased, and IL-3-biased production, and a pattern that switches over a period of days from GM-CSF-biased to IL-3-biased production; 3) the disparate relative levels of secretion are not due to differential consumption of either cytokine; 4) altered T cell activation by addition of CD28 costimulation accelerates both GM-CSF and IL-3 production but biased patterns of expression are retained, and 5) most T cells are not pre-committed to a particular pattern of relative GM-CSF and IL-3 expression; instead, the potential for multiple patterns may persist for several days following in vitro activation. The results indicate that T cells have the potential to display previously unrecognized diversity of expression of GM-CSF and IL-3.
Regulation of JAK3 expression and activation in human B cells and B cell malignancies.
Authors: Tortolani P J , Lal B K , Riva A , Johnston J A , Chen Y Q , Reaman G H , Beckwith M , Longo D , Ortaldo J R , Bhatia K , McGrath I , Kehrl J , Tuscano J , McVicar D W , O'Shea J J 
Published: December 2022

Abstract
Members of the Janus family (JAK) of protein tyrosine kinases are critical enzymes in signaling pathways via hematopoietin receptors. We have cloned JAK3, which unlike other known family members (JAK1, JAK2, and TYK2) is preferentially expressed in hematopoietic cells but not in a variety of other cells. Functionally, JAK3 and JAK1 are coupled to the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 in T cells and NK cells. Because of the importance of IL-2, IL-4, and IL-7 in B cell physiology, we sought to determine whether JAK3 was also present in B lymphocytes and whether it was involved in signaling via cytokines that are important for B cell development and function. In this report, we demonstrate that JAK3 is expressed in normal human peripheral blood B cells at levels that are comparable to those in T cells. In addition, the levels were found to be markedly up-regulated following stimulation with staphylococcal protein A Cowan and anti-CD40 Abs. In addition, IL-4 and IL-7 induced the rapid tyrosine phosphorylation of JAK3 and JAK1, and IL-4 activated both JAK3 and JAK1 phosphotransferase activity. JAK3 protein was also detected in immature B cell lines, but not in more well differentiated cell lines. Additionally, JAK3 was detected in lysates from bone marrow lymphoblasts of patients with B cell precursor acute lymphocytic leukemia and cell lines derived from human B cell lymphomas. Together, these data suggest that the regulation of JAK3 expression and activity is likely to be important in B cell development and function.
Similar but nonidentical amino acid residues on vascular cell adhesion molecule-1 are involved in the interaction with alpha 4 beta 1 and alpha 4 beta 7 under different activity states.
Authors: Chiu H H , Crowe D T , Renz M E , Presta L G , Jones S , Weissman I L , Fong S 
Published: December 2022

Abstract
The integrin receptors alpha 4 beta 1 and alpha 4 beta 7 both bind to vascular cell adhesion molecule-1 (VCAM-1). Here, we report that the amino acid residue requirements for murine VCAM-1 adhesion to murine alpha 4 beta 1 (WEHI 231) and alpha 4 beta 7 (38C13/beta 7-transfectant) positive cells are strikingly similar but nonidentical under multiple adhesion activity states. By site-directed mutagenesis of domain 1 of VCAM-1, the amino acid residues on the loop between beta strands C and D (R36, Q38, I39, D40, P42) and on the adjacent antiparallel beta strand F (L70 and T72) were required for basal level adhesion to both alpha 4 beta 1-positive and alpha 4 beta 7-positive cells. Mutation at two other sites, N44 (loop between beta strands C and D) and E66 (loop between beta strands E and F), specifically reduced alpha 4 beta 7-positive cell adhesion, but not alpha 4 beta 1-positive cell adhesion. Mutation H85A augmented alpha 4 beta 7 binding but not alpha 4 beta 1 binding. These apparent differences relate to the higher intrinsic activity state of alpha 4 beta 1 on WEHI 231 than on alpha 4 beta 7 (38C13/beta 7-transfectant). In contrast, under higher adhesion activity states induced by either MnCl2 or truncation of the beta 7 cytoplasmic tail, mutation of either amino acid residue D40 or L70 completely blocked cell adhesion without evidence of structural perturbation of VCAM-1. These results suggested that the two structurally discontinuous amino acid residues, the negatively charged D40 and the hydrophobic L70 adjacently located on domain 1 of VCAM-1, are essential for interaction under multiple activity states with both alpha 4 beta 1 and alpha 4 beta 7 integrin receptors.
Recombinant human growth-regulated oncogene-alpha induces T lymphocyte chemotaxis. A process regulated via IL-8 receptors by IFN-gamma, TNF-alpha, IL-4, IL-10, and IL-13.
Authors: Jinquan T , Frydenberg J , Mukaida N , Bonde J , Larsen C G , Matsushima K , Thestrup-Pedersen K 
Published: December 2022

Abstract
The human cytokine growth-regulated oncogene (GRO)-alpha is a small glycoprotein secreted by monocytes, endothelial cells, glycoprotein secreted by monocytes, endothelial cells, fibroblasts, synovial cells, and some tumor cells such as melanoma cells. It is structurally related to IL-8 and can activate neutrophils, whereas it induces chemotaxis, exocytosis, and a respiratory burst in neutrophils. To date, its functions on T lymphocytes have not been well established. We report here that recombinant human (rh)GRO-alpha is a potent chemoattractant for freshly isolated T lymphocytes, but not for anti-CD3 mAb-activated T lymphocytes. It attracts CD4+ and CD8+ T lymphocyte subsets to an equal extent. The migrating T lymphocytes toward rhGRO-alpha are predominantly CD45RO+ memory CD4+ and CD8+ subsets. The chemotactic migration of T lymphocytes toward rhGRO-alpha is stimulated via the IL-8 receptors on the cells. This process can be augmented by IFN-gamma and TNF-alpha, and inhibited by IL-4, IL-10, and IL-13. In addition, we also document that on T lymphocytes there exist IL-8 receptors that can be up-regulated by IFN-gamma, TNF-alpha, and IL-2. Our results demonstrate that rhGRO-alpha gene encodes for an inflammatory mediator that stimulates the directional migration of T lymphocytes. It may thus be another important mediator in the diseases in which T lymphocytes form the major constituent of the cellular infiltration.