bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression and regulation of the neural cell adhesion molecule L1 on human cells of myelomonocytic and lymphoid origin.
Authors: Pancook J D , Reisfeld R A , Varki N , Vitiello A , Fox R I , Montgomery A M 
Published: December 2022

Abstract
The neural cell adhesion molecule L1 has been implicated in a variety of neurologic processes, including neuritogenesis and cerebellar cell migration. Here we propose an expanded role for this cell adhesion molecule in the human immune system based on its expression on cells of myelomonocytic and lymphoid origin. Freshly isolated circulating monocytes had minimal L1 expression; however, activation of these effector cells by IFN-gamma, or as a result of density gradient isolation, resulted in a significant induction of L1 expression. Constitutive L1 expression was further evident on myelomonocytic cell lines but was absent on mature tissue macrophages. In further studies, positive selection with a L1-specific Ab enriched both B cells and dendritic precursor cells from peripheral blood. Significantly, L1 expression was not detected on mature dendritic cells but could be induced by treatment with LPS, PHA, and TNF-alpha. Immunohistochemical analysis further demonstrated significant L1 expression on follicular dendritic cells and on endothelial cells associated with the arterioles and red pulp of normal spleen. Based on these observations and known functions of L1, we propose that this cell adhesion molecule may contribute to cell-cell adhesion events associated with the effector function or extravasation of these immune effector cells. In support of the latter, we present evidence that L1 can be recognized by endothelial cells via the integrin alpha(v)beta3.
CD14-dependent and CD14-independent signaling pathways in murine macrophages from normal and CD14 knockout mice stimulated with lipopolysaccharide or taxol.
Authors: Perera P Y , Vogel S N , Detore G R , Haziot A , Goyert S M 
Published: December 2022

Abstract
The antitumor agent, Taxol, shares with bacterial LPS the ability to activate murine macrophages, and its LPS-mimetic effects are blocked by LPS analogue antagonists. Since CD14 is central to the recognition of LPS by macrophages, we sought to examine a role for CD14 in the response to Taxol vs LPS. A comparison of responses of macrophages from wild-type mice with those from mice lacking CD14 due to a targeted disruption of the CD14 gene (CD14-deficient knockout (CD14KO)) revealed that like LPS, Taxol induces both CD14-dependent and -independent pathways of gene activation, although the CD14 dependency of Taxol stimulation is much less striking than that observed with LPS. The macrophage interaction with low concentrations of LPS (&lt; or = 10 ng/ml) is largely CD14 dependent, as evidenced by the lack of induction of TNF-alpha, IL-1beta, and interferon-inducible protein-10 (IP-10) genes by CD14KO macrophages cultured in the absence of soluble CD14 (i.e., in autologous CD14KO -/- mouse serum). However, at high concentrations of LPS or Taxol, a CD14-independent pathway of activation is observed: this pathway leads to minimal IP-10 gene induction, even though induction of TNF-alpha and IL-1beta occurs. Measurements of TNF secretion followed a similar pattern to that observed at the level of steady state mRNA. These data suggest the existence of two pathways of activation by both LPS and Taxol: one that is CD14 dependent and leads to induction of TNF-alpha, IL-1beta, and IP-10 gene induction, and a CD14-independent pathway that results in the induction of TNF-alpha and IL-1beta, with minimal induction of IP-10.
Effects of sleep and circadian rhythm on human circulating immune cells.
Authors: Born J , Lange T , Hansen K , Mölle M , Fehm H L 
Published: December 2022

Abstract
The role of nocturnal sleep for normal immune regulation and its relation to circadian rhythm was examined in 10 men participating in two 51-h sessions. One session included two regular wake-sleep cycles; the other included a night of sustained wakefulness followed by a night of recovery sleep. Blood was collected every 3 h to determine PBMC counts, including the enumeration of monocytes, NK cells, and lymphocyte subsets (CD19+, CD3+, CD4+, CD8+, HLA-DR+). Production of IL-1beta, TNF-alpha, IL-2, and IFN-gamma was determined after stimulation of whole blood samples with LPS and PHA, respectively. Concentrations of IL-6 and cortisol were assessed in plasma. Enumeration of cells indicated significant circadian rhythms for all PBMC subsets under conditions of sustained wakefulness. Compared with sustained wakefulness, nocturnal sleep acutely reduced the numbers of monocytes, NK cells, and counts of all lymphocyte subsets. However, in the afternoon and evening of the day following sleep, counts of NK cells and lymphocytes were significantly higher than after nocturnal wakefulness, indicating that effects of sleep interacted with those of the circadian pacemaker. Sleep markedly enhanced production of IL-2 by T cells (CD3+) but did not influence production of IL-1beta and TNF-alpha, or IL-6 concentrations. Effects of sleep were not mediated by changes in cortisol. The decrease in monocytes, NK cells, and lymphocytes, together with an increased production of IL-2 during sleep, may serve to support ongoing immune defense in extravascular lymphoid tissue during a time of diminished acute Ag challenge.
C-C chemokines, IL-16, and soluble antiviral factor activity are increased in cloned T cells from subjects with long-term nonprogressive HIV infection.
Authors: Scala E , D'Offizi G , Rosso R , Turriziani O , Ferrara R , Mazzone A M , Antonelli G , Aiuti F , Paganelli R 
Published: December 2022

Abstract
A combination of three beta, or C-C, chemokines, as well as IL-16, have been shown to inhibit HIV replication in vitro. Cellular antiviral factor is a more potent agent, and acts on all HIV strains. All are mainly, but not exclusively, produced by CD8+ T cells, both in HIV+ and healthy subjects. We studied the production of these HIV-suppressive factors in patients with HIV infection at different stages of disease. No difference in production by PBMC stimulated with PHA has been observed in asymptomatic HIV+, long-term nonprogressors (LTnP), and AIDS patients. When T cell line supernatants from these three groups were studied, no significant difference was found for C-C chemokines or IL-16 production, and viral suppression. However, T cell clones from LTnP secreted higher levels of all three chemokines, IL-16, and exerted a stronger inhibition on HIV replication. CD8+ clones showed a higher production than CD4+ clones. These clones were able to produce all antiviral factors irrespective of the secretion of type 1 or type 2 cytokines. The antiviral activities were not correlated, implying that viral suppression did not depend solely on C-C chemokines or IL-16. We postulate that all factors are needed to prevent HIV disease progression.
xid affects events leading to B cell cycle entry.
Authors: Brorson K , Brunswick M , Ezhevsky S , Wei D G , Berg R , Scott D , Stein K E 
Published: December 2022

Abstract
X-linked agammaglobulinemia patients and X-linked immunodeficient (xid) mice possess mutations in the Bruton's tyrosine kinase (Btk kinase) gene and display defects in B cell development and activation by sIg cross-linking. Btk is an early activation kinase in sIg-cross-linked B cells. xid does not ablate Btk protein kinase activity, and immediate signal transduction events, such as tyrosine phosphorylation, occur in sIg-activated xid B cells. These cells do not subsequently progress into cell division and have a high rate of apoptosis, which has been shown to correlate with an absence of sIg-mediated induction of the bcl-xL protein. To establish the point where Btk activity is critical for progression beyond immediate signaling, we examined early and late events in sIg-cross-linked xid B cells. Induction of proto-oncogenes and nuclear factors occurred normally in xid cells. However, induction of cyclins and increased GAPDH mRNA was not observed in xid cells. Degradation of the cyclin inhibitor p27Kip1 occurred normally in xid cells. After 24 h of culture with anti-mu, the remaining live, nonapoptotic xid cells were enlarged, viable, and primed for subsequent stimulation by LPS. Our data suggest that the Btk kinase is not essential for several G1 events and that the failure of sIg-activated xid B cells to enter cell cycle correlates with a defect of cyclin induction. Moreover, these data suggest that Btk is important not only for immediate events following B cell activation and control of apoptosis but also for subsequent events leading to cyclin activation.
CD38 ligation in human B cell progenitors triggers tyrosine phosphorylation of CD19 and association of CD19 with lyn and phosphatidylinositol 3-kinase.
Authors: Kitanaka A , Ito C , Coustan-Smith E , Campana D 
Published: December 2022

Abstract
CD38 is a 45-kDa transmembrane glycoprotein highly expressed in lymphoid progenitors. Ligation of CD38 with specific Abs inhibits growth and induces apoptosis in human immature B cells. CD38 ligation also triggers tyrosine phosphorylation of syk, c-cbl, and phospholipase C-gamma and activates phosphatidylinositol 3-kinase (PI3-K). In the present study, we investigated whether the cell surface membrane molecules used in B cell receptor-mediated signaling, such as Ig alpha, Ig beta, and CD19, could be involved in the CD38-mediated signaling cascade. In the B cell receptor-negative immature B cell lines RS4;11, 380, and REH, Ig alpha and Ig beta were expressed exclusively in the cytoplasm and were not tyrosine phosphorylated after CD38 ligation. By contrast, CD19 was markedly tyrosine phosphorylated and was associated with lyn and PI3-K. PI3-K activation appears to be directly linked to the growth-arresting effects of CD38 ligation, which are reduced by PI3-K inhibitors. Ligation of either CD38 or CD19 resulted in a similar pattern of protein tyrosine phosphorylation; both signaling pathways caused tyrosine phosphorylation of c-cbl. Levels of CD38 surface expression were not affected by prolonged incubation with anti-CD19 Ab, while CD19 expression markedly decreased. These results indicate that CD19 is a major component of the CD38 signaling cascade in B cell precursors, serving as a cell surface membrane docking site for cytoplasmic kinases. CD38 and CD19 are not physically linked, but activate an overlapping set of kinases in human immature B cells.
The immunosuppressive metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms.
Authors: Elder R T , Xu X , Williams J W , Gong H , Finnegan A , Chong A S 
Published: December 2022

Abstract
The immunosuppressive metabolite of leflunomide, A77 1726, inhibits the enzymatic activity of protein tyrosine kinases and of dihydro-orotic acid dehydrogenase, an enzyme involved in pyrimidine biosynthesis. Here murine CTLL cell lines were studied to determine which of the biochemical targets of A77 1726 was responsible for the observed inhibition of proliferation and cytotoxic activity. At low concentrations of A77 1726, pyrimidine biosynthesis is the target, since inhibition of proliferation correlates with a reduction in pyrimidine NTP levels and is reversed by uridine. At higher concentrations of A77 1726, uridine no longer reverses the inhibition of proliferation even though pyrimidine NTP levels are restored. This second mechanism for inhibiting proliferation is probably inhibition of protein tyrosine kinases, since these higher concentrations of A77 1726 inhibit IL-2-induced tyrosine phosphorylation of Jak1 and Jak3, the protein tyrosine kinases initiating signaling by the IL-2R. Tyrosine phosphorylation of the beta-chain of the IL-2R, which is required for IL-2-driven proliferation, is also inhibited by A77 1726. Cytotoxicity of a CTLL line that overexpresses the Lck protein tyrosine kinase is inhibited by A77 1726; this inhibition is not affected by uridine, but does correlate with inhibition of an Lck in vitro kinase reaction. These studies establish that inhibition of pyrimidine biosynthesis and that of protein tyrosine kinase both contribute to the effects of A77 1726 on CTLL cell lines.
Human alveolar T lymphocyte responses to Mycobacterium tuberculosis antigens: role for CD4+ and CD8+ cytotoxic T cells and relative resistance of alveolar macrophages to lysis.
Authors: Tan J S , Canaday D H , Boom W H , Balaji K N , Schwander S K , Rich E A 
Published: December 2022

Abstract
T cell-mediated cytotoxicity against Mycobacterium tuberculosis (MTB)-infected macrophages may be a major mechanism of specific host defense, but little is known about such activities in the lung. Thus, the capacity of alveolar lymphocyte MTB-specific cell lines (AL) and alveolar macrophages (AM) from tuberculin skin test-positive healthy subjects to serve as CTL and target cells, respectively, in response to MTB (H37Ra) or purified protein derivative (PPD) was investigated. Mycobacterial Ag-pulsed AM were targets of blood CTL activity at E:T ratios of &gt; or = 30:1 (51Cr release assay), but were significantly more resistant to cytotoxicity than autologous blood monocytes. PPD- plus IL-2-expanded AL and blood lymphocytes were cytotoxic for autologous mycobacterium-stimulated monocytes at E:T ratios of &gt; or = 10:1. The CTL activity of lymphocytes expanded with PPD was predominantly class II MHC restricted, whereas the CTL activity of lymphocytes expanded with PPD plus IL-2 was both class I and class II MHC restricted. Both CD4+ and CD8+ T cells were enriched in BL and AL expanded with PPD and IL-2, and both subsets had mycobacterium-specific CTL activity. Such novel cytotoxic responses by CD4+ and CD8+ T cells may be a major mechanism of defense against MTB at the site of disease activity.
Defective TCR stimulation in anergized type 2 T helper cells correlates with abrogated p56(lck) and ZAP-70 tyrosine kinase activities.
Authors: Faith A , Akdis C A , Akdis M , Simon H U , Blaser K 
Published: December 2022

Abstract
Development of IgE-mediated allergic conditions is dependent on the secretion of a Th2 cytokine pattern, including IL-4, IL-5, and IL-13. The induction of anergy would be one mechanism to abrogate cytokine secretion by Th2 cells, which may be pivotal to the allergic response. We demonstrate here that incubation of cloned human CD4+ phospholipase A2 (PLA)-specific Th2 cells with antigenic peptide, in the absence of professional APC, results in a state of nonresponsiveness. The anergic T cells failed to proliferate or secrete IL-4 in response to optimal stimulation with PLA and autologous, professional APC. Secretion of IL-5 and IL-13, however, was only partially inhibited. The anergic state of the Th2 cells was not associated with CD3 or CD28 down-regulation. However, anergy did appear to be closely related to alterations in signaling pathways, mediated through the TCR, of the cells. In contrast to untreated Th2 cells, anergized Th2 cells failed to respond to anti-CD3 mAb with either increased tyrosine kinase activity or increased levels of tyrosine phosphorylation of p56(lck) or ZAP70. A strong and sustained intracellular calcium flux, observed in untreated Th2 cells in response to anti-CD3 mAb, was absent in anergic Th2 cells. Furthermore, the induction of anergy seems to represent an active process, associated with increased levels of basal tyrosine kinase activity, cytokine production, and CD25 up-regulation in anergic Th2 cells. Together, our results indicate that anergy in Th2 cells is associated with defective transmembrane signaling through the TCR.
TNF-alpha bifunctionally induces proliferation in primary hepatocytes: role of cell anchorage and spreading.
Authors: Watanabe Y , Osaki H , Akaike T 
Published: December 2022

Abstract
In the absence of a growth factor or an appropriate extracellular matrix (ECM), cells are arrested in the G0/G1 phase. In this report, we demonstrate the evidence that TNF-alpha induced DNA synthesis of primary mouse hepatocytes in vitro by activating two distinct pathways. TNF-alpha induced drastic spreading of hepatocytes on hydrophobic plastic, while the adhesion was not influenced. The effect was time and dose dependent. The cell spreading was accompanied by the phosphorylation of paxillin, indicating the stimulation of focal adhesion molecules. TNF-alpha-induced spreading of hepatocytes was not transient, and kinetic analysis and morphologic observation suggest that the effect was different from epidermal growth factor- or hepatocyte growth factor-induced transient hepatocyte spreading. TNF-alpha-induced hepatocyte spreading was blocked by cytochalasin D, Arg-Gly-Asp peptides, cycloheximide, or anti-integrin beta1 Ab. Results of competitive PCR for ECM proteins demonstrated that TNF-alpha increased the expression of laminin alpha3 and gamma1 chains in hepatocytes. These data suggested that TNF-alpha induced cell anchorage for hepatocytes by up-regulating ECM production. More importantly, TNF-alpha, but neither epidermal growth factor nor hepatocyte growth factor, induced DNA synthesis following the spreading in primary hepatocytes on hydrophobic plastic, while mere cell spreading on collagen did not induce DNA synthesis. The DNA synthesis was blocked by the inhibition of either cell spreading or DNA polymerase, demonstrating that TNF-alpha induced DNA synthesis in primary hepatocytes by activating two distinct pathways, i.e., forming the scaffold and inducing growth signals. Taken together, TNF-alpha bifunctionally regulates the proliferation of primary hepatocytes, serving as both an ECM inducer and a growth factor.
Expansion of mature thymocyte subsets before emigration to the periphery.
Authors: Pénit C , Vasseur F 
Published: December 2022

Abstract
A small population of DNA-synthesizing mature thymocytes could be defined by analyzing cell surface markers and 5-bromo-2'-deoxyuridine (BrdUrd) labeling by four-color cytofluorometry. These cells have a completely mature phenotype (CD4- CD8+ or CD4+ CD8- TCR(high), HSA-, Qa-2(high)) and expand only weakly after BrdUrd incorporation. They recovered immediately in total number and in DNA synthesis rate after treatment with the antimitotic drug demecolcin, thus much faster than immature CD4+ CD8+ thymocytes. These data demonstrate the existence of a late intrathymic expansion phase, independent of that of developing CD4+ CD8+ immature cells, and involving phenotypically mature cells renewed each day. In mixed chimeras prepared by transfer of bone marrow and lymph node cells into RAG-2(-/-) mice, all cycling mature thymocytes were bone marrow derived. They are thus produced in situ and do not correspond to peripheral T cells reentering the thymus. Double FITC/BrdUrd detection showed that a high proportion (10-20%) of recent thymic emigrants were BrdUrd+ just postcycling cells and that around 50% of cycling mature thymocytes are just ready to emigrate to the periphery in the few hours after DNA synthesis. The late intrathymic expansion phase demonstrated here increases the daily thymic cell export by at least 30%. It could play a role in the adjustment of the T cell repertoire before emigration and in the regulation of the thymic cell output into the peripheral T cell pool.
Autoantigen recognition by human CD8 T cell clones: enhanced agonist response induced by altered peptide ligands.
Authors: Dressel A , Chin J L , Sette A , Gausling R , Höllsberg P , Hafler D A 
Published: December 2022

Abstract
Determination of immunodominant epitopes of MHC class I-restricted self-Ags and elucidation of TCR contact residues is of potential importance in providing a means of manipulating the immune response to self-Ags in human autoimmune diseases. A computer algorithm was used to examine the sequences of the two major encephalitogenic proteins of myelin, MBP and PLP, for HLA-A2 binding motifs. Thirty-eight peptides with HLA-A2.1 binding motifs were synthesized and their binding to HLA-A2.1 was measured. A panel of HLA-A2-restricted T cell clones directed against the PLPp80-88 epitope, which exceeded the binding affinity of the other myelin-peptides tested by at least one order of magnitude, was generated. Using a set of analogue peptides with single amino acid substitutions, we detected a distinct pattern of TCR contact residues for each clone. Surprisingly, modification of different presumed TCR contact residues generated superagonist peptides, which are defined as peptides with equal or lower MHC binding affinity to HLA-A2 that induce half-maximal effector responses at 100-fold lower concentrations than the original peptide. These agonist peptides could drive cytotoxic T cell clones to proliferate, secrete cytokines, and clonally expand at concentrations at which the native peptide induced only cytotoxic responses. The proliferation induced by the superagonist peptides gives additional evidence that the clonal expansion of CD8 T cell clones may in part be regulated on the level of Ag recognition by the TCR.
Costimulation provided by DNA immunization enhances antitumor immunity.
Authors: Corr M , Tighe H , Lee D , Dudler J , Trieu M , Brinson D C , Carson D A 
Published: December 2022

Abstract
The interaction of the TCR with MHC class I-bound Ag is insufficient for the priming of CTL unless secondary costimulatory signals are provided. To ascertain the minimum elements required to activate an Ag-specific CTL response in vivo, we injected mice intradermally or i.m. with plasmid DNA encoding a MHC class I-restricted peptide Ag (minigene) and different membrane-bound costimulatory ligands. The minigene-encoded epitope only primed a specific CTL response if injected in the vicinity of an ectopically expressed costimulatory ligand. Vector encoding B7-1 was repeatedly more potent at stimulating a cytolytic response than vector encoding B7-2. In contrast the B7-2-encoding plasmid preferentially enhanced Ag-specific Ab responses when injected with either protein or a cDNA expression vector. Gene vaccination with plasmids encoding OVA and B7-1, but not B7-2, prolonged survival in mice challenged with an OVA-transfected tumor. These results show that functional B7-1 transfection can be achieved in vivo and induces the selective induction of CTL. The data suggest that B7-1 plasmids should be coadministered with naked DNA vaccines that aim to induce tumor-specific cellular immunity.
SCID mice reconstituted with IL-4-deficient lymphocytes, but not immunocompetent lymphocytes, are resistant to cutaneous leishmaniasis.
Authors: Satoskar A , Brombacher F , Dai W J , McInnes I , Liew F Y , Alexander J , Walker W 
Published: December 2022

Abstract
To characterize the roles of lymphoid- and non-lymphoid-derived IL-4 during cutaneous infection with Leishmania mexicana, the disease was monitored in SCID mice reconstituted with splenocytes from either immunocompetent BALB/c mice or IL-4-deficient BALB/c mice. Whereas following s.c. infection with L. mexicana no lesion growth was observed in BALB/c IL-4(-/-) mice and lesion growth was significantly inhibited in SCID mice, rapid initial lesion growth occurred in both SCID IL-4(+/+) and SCID IL-4(-/-) reconstituted mice. However, after 3 to 4 wk of infection, lesions in SCID IL-4(-/-) but not SCID IL-4(+/+) reconstituted mice began to heal. This paralleled a developing Th1-like phenotype and parasite clearance in the former group and a developing Th2-like phenotype in the latter group. Lesion sites from the healing SCID IL-4(-/-) mice expressed the inducible nitric oxide synthase, whereas the SCID IL-4(+/+) mice with progressive disease did not. These findings indicate that non-lymphocyte-derived IL-4 may play a role in initiating lesion growth following cutaneous infection with L. mexicana, but the presence of lymphocyte-derived IL-4 is essential for disease progression, and in its absence, lesions heal due to a developing Th1 phenotype.