bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular basis for a familial defect in phagocyte expression of IgG receptor I (CD64).
Authors: van de Winkel J G , de Wit T P , Ernst L K , Capel P J , Ceuppens J L 
Published: December 2022

Abstract
Four individuals have been identified, within a single family, who lack phagocyte expression of the high affinity type I IgG receptor (CD64). As a result, their monocytes are unable to support mouse IgG2a anti-CD3-induced T cell mitogenesis (nonresponder individuals). Southern blotting proved all three human Fc gamma receptor I (hFc gamma RI) genes to be present in nonresponders without major structural changes. Nucleotide sequencing showed identical hFc gamma RIA promoter regions in all individuals. At the message level, a distinct difference was noted between monocytes from control (responder) donors and from nonresponders. Both a 1.7- and 1.6-kb message were found in responders, whereas in nonresponders only the 1.6-kb species was detectable. Reverse transcriptase-PCR analyses showed the hFc gamma RIa transcript (encoding a receptor with three extracellular Ig-like domains) to be present at a approximately 15- to 20-fold lower level in nonresponder monocytes. Importantly, we found a single nucleotide difference (C --&gt; T) within the extracellular domain exon 1-encoding region of hFc gamma RIA in nonresponders, resulting in the change of codon 92 (encoding an arginine) into a termination codon. This change likely affects mRNA stability and, thereby, leads to undetectable expression of phagocyte-hFc gamma RIa. Despite this defect, these individuals are apparently healthy, suggesting that hFc gamma RIa is dispensable for phagocyte functioning.
TCR-stimulated naive human CD4+ 45RO- T cells develop into effector cells that secrete IL-13, IL-5, and IFN-gamma, but no IL-4, and help efficient IgE production by B cells.
Authors: Brinkmann V , Kristofic C 
Published: December 2022

Abstract
It is currently believed that IgE production by B cells is induced by activated CD4+ Th2-like cells that produce increased amounts of IL-4 but low levels of IFN-gamma. We found that "naive" CD4+ 45RO- T cells primed and restimulated in vitro via the TCR developed into effector cells that produced large amounts of IL-13, IL-5, and IFN-gamma, but no IL-4. Such CD4 T cells induced surface IgD+E- B cells to produce large amounts of IgE. The IgE response could be blocked completely by neutralizing anti-IL-13 Abs, whereas anti-IL-4 had no effect. Addition of exogenous IL-4 during priming of CD4 cells suppressed clonal expansion and the development of Th cells including helpers for IgE, but increased endogenous production of IL-4 and IL-5, and suppressed production of IFN-gamma. Addition of exogenous IFN-alpha, IFN-gamma, or neutralizing anti-IFN-gamma mAbs affected neither priming of CD4 T cells nor B cell help. In contrast to CD4+ 45RO- naive T cells, CD4+ 45RO+ "memory" T cells primed and restimulated in vitro secreted IL-4 in addition to IL-13, IL-5, and IFN-gamma, and the IgE response induced by such cells could be blocked only by a combination of anti-IL-4 plus anti-IL-13 Abs. Unlike CD4 cells, CD8 cells could not be primed to help IgE production. The results indicate that TCR/CD3 cross-linking on naive human CD4 T cells is sufficient to induce the development of potent IgE helper cells, which secrete large amounts of IL-13, IL-5, and IFN-gamma, but no IL-4. Such Th cells may exacerbate atopic inflammation, because all by themselves they could drive IL-13-dependent IgE production, IL-5-dependent eosinophilia, and IFN-gamma-dependent macrophage activation, but could not suppress IFN-gamma production by other T cells via IL-4.
Expression and induction of nuclear factor-kappa B-related proteins in thymocytes.
Authors: Sen J , Venkataraman L , Shinkai Y , Pierce J W , Alt F W , Burakoff S J , Sen R 
Published: December 2022

Abstract
Thymocytes mature in response to the cues from the thymic micro-environment, which regulate stage-specific gene expression during development. We find that several proteins that bind the kappa B sequence in vitro are constitutively activated in freshly isolated thymocytes. These include the rel-related p50 homodimers, p50/p65 heterodimers, low levels of c-rel, and two other factors that may be thymus specific. Disruption of the thymic micro-environment resulted in loss of DNA-binding, suggesting that lymphocyte-stromal cell interactions induce and maintain these proteins in a DNA-binding form. Phorbol ester and ionomycin treatment induced p50, p65, and p68 c-rel kappa B DNA-binding activity. Expression of p68 c-rel protein, but not p50 or p65, was suppressed by the immunosuppressive drug FK506. Because FK506 specifically inhibits the appearance of mature single-positive thymocytes, gene expression regulated by p68 c-rel may play a role in selection and maturational signals involved in the double-positive to single-positive transition.
Translational regulation of murine complement factor B alternative transcripts by upstream AUG codons.
Authors: Garnier G , Circolo A , Colten H R 
Published: December 2022

Abstract
Factor B (Bf), a constituent of the alternative pathway of complement activation, is encoded by a single gene that is located within the MHC. In murine kidney and intestine, two Bf transcripts (Bf short and Bf long), generated from distinct transcriptional initiation sites, are expressed in approximately equal amounts. In the liver, &gt; 95% of Bf mRNA is the short transcript. To ascertain the biologic consequences of this tissue-specific mRNA polymorphism, we quantitated the effect of structural differences between the two transcripts on net Bf protein synthesis. Cell-free translation of Bf mRNA in vitro revealed that the rate of translation of Bf short is about twice that of Bf long. The 5' extension of Bf long includes four short open reading frames upstream of the authentic translational initiation codons. Mutation of all four upstream AUGs generates a Bf long transcript with a translational rate about equal to that of Bf short. This effect was primarily accounted for by mutation of the second AUG from the 5' end. Similar studies of Bf expression in vivo showed an approximately twofold difference in translational rate between Bf long and the transcript mutated at the upstream AUGs. Because systemic and local inflammation in kidney alters the ratio of Bf long and short, net production of complement protein Bf in extrahepatic tissues is regulated by both transcriptional and translational control mechanisms.
A novel phosphocholine antigen protects both normal and X-linked immune deficient mice against Streptococcus pneumoniae. Comparison of the 6-O-phosphocholine hydroxyhexanoate-conjugate with other phosphocholine-containing vaccines.
Authors: Fischer R T , Longo D L , Kenny J J 
Published: December 2022

Abstract
A novel form of phosphocholine (PC), p-nitrophenyl-6-(O-phosphocholine)hydroxyhexanoate (EPC) coupled to keyhole limpet hemocyanin (KLH) has been compared with unencapsulated, avirulent Streptococcus pneumoniae (R36a) and with the traditional thymus-dependent form of PC, diazophenylphosphocholine (DPPC)-conjugated KLH for its vaccine potential against virulent S. pneumoniae. Immunization with any of these three PC-containing Ags protects normal mice against a lethal challenge with 10(4) S. pneumoniae, whereas only EPC-KLH provides total protection to Xid mice. DPPC-KLH and unencapsulated S. pneumoniae confer less than 40% protection in Xid mice. Passive transfer of a PC-specific hybridoma Ab made from EPC-KLH-immunized Xid mice also provided protection against lethal challenge with S. pneumoniae. Protective anti-PC Ab were capable of binding to the surface of virulent bacteria, whereas anti-PC Ab incapable of binding to the bacterial surface failed to protect. Furthermore, serum Ab from EPC-KLH immunized and protected mice bound to S. pneumoniae, whereas secondary Abs from DPPC-KLH- or R36a-immunized mice failed to bind to the bacteria. EPC-KLH is potentially a vaccine candidate for pneumococcal prophylaxis in settings of immune compromise.
Analysis of clonal CD8+ T cell expansions in normal individuals and patients with rheumatoid arthritis.
Authors: Fitzgerald J E , Ricalton N S , Meyer A C , West S G , Kaplan H , Behrendt C , Kotzin B L 
Published: December 2022

Abstract
In the course of studying the circulating TCR repertoire in humans, we noted several individuals with an increase in the percentage of CD8+ T cells expressing a particular V region. In some cases, these CD8 expansions were dramatic, occupying over 40% of the total CD8 repertoire. Using a panel of mAbs to different TCR V regions, we found that over 30% of healthy adults (&gt; 35 years of age) harbor an expansion that alters the peripheral blood CD8 TCR repertoire. A wide range of V regions were expressed by these expansions. Considering that the mAbs used cover only a portion of the V beta repertoire, the data suggest that over 70% of adults are likely to harbor such expansions. Junctional region sequencing showed that the CD8 subset expansions were clonal, and serial studies as long as 4 years showed that they persisted indefinitely. Expansions were not identified in the CD4 population. Discordant expression of one large V beta 6.7+ clone was found in one identical twin set, suggesting the possibility that an environmental exposure is involved in their generation and/or expansion. In one large family, we found five family members with a large CD8 subset expansion. Remarkably similar usage of J beta regions was noted, and two individuals demonstrated V beta 3-expressing clones with homologous CDR3 regions, differing by only one major substitution. The repertoire data from this family suggest that the T cell clones have arisen in response to a common Ag. Studies of patients with rheumatoid arthritis found a significantly increased frequency of circulating CD8 subset expansions that expressed a different V region repertoire compared with the healthy individuals studied. Overall, our results emphasize a frequent alteration in the human CD8 TCR repertoire, most likely related to an environmental exposure, in both healthy individuals and patients with rheumatoid arthritis. The presence of these expansions will be important to consider in any study of human TCR repertoire, and their implication for health and disease will be important to understand.
Regulated expression of Ly-6A.2 is important for T cell development.
Authors: Bamezai A , Palliser D , Berezovskaya A , McGrew J , Higgins K , Lacy E , Rock K L 
Published: December 2022

Abstract
Ly-6A.2 is a surface protein on T cells that may play a role in lymphocyte activation. The regulation of Ly-6A.2 expression during T cell lymphopoiesis has been intriguing. It is one of the earliest markers expressed on pluripotent hemopoietic stem cells and is present on both primitive and mature T cells, but its expression is extinguished in the thymus during key developmental stages. To determine whether Ly-6A.2 is active on developing T cells, as well as the significance of its developmental regulation, Ly-6A.2 was expressed throughout T cell development under control of the T cell-specific human CD2 enhancer in transgenic mice. The constitutive overexpression of Ly-6A.2 in vivo led to a marked impairment in the generation of thymocytes. Development was arrested at the time in thymic development when Ly-6A.2 expression is normally turned off. These results indicate that the regulated expression of Ly-6A.2 in thymocytes may be important for normal development. Moreover, these findings demonstrate that Ly-6A.2 is active in the thymic microenvironment.
IL-10 prevents naturally occurring fetal loss in the CBA x DBA/2 mating combination, and local defect in IL-10 production in this abortion-prone combination is corrected by in vivo injection of IFN-tau.
Authors: Chaouat G , Assal Meliani A , Martal J , Raghupathy R , Elliott J F , Elliot J , Mosmann T , Wegmann T G 
Published: December 2022

Abstract
CBA x DBA/2 placentae are quantitatively or qualitatively deficient in their production of the anti-inflammatory Th2-type cytokines IL-4 and IL-10 compared with the nonresorption-prone CBA x BALB/c mating combination. Wastage in this mating combination is accompanied by increased levels of local inflammatory cytokines. In addition, alloimmunization enhances the placental production of IL-4 and IL-10 in CBA x DBA/2 matings. Furthermore, rIL-10 by itself completely reverses the high incidence of fetal resorption after i.p. injection. Conversely, anti-IL-10 increases the resorption rate, but only in CBA x DBA/2 matings. On the other hand, injecting either anti-IFN-gamma or pentoxifillin (an anti-TNF agent) partially reduces the resorption. When given together, they produce a synergistic remission of fetal loss. Finally, we report that recombinant ovine trophoblast protein, an IFN-tau which is known to influence reproductive outcome in ruminants, can also counteract increased CBA x DBA/2 fetal resorption. It simultaneously induces increased placental IL-4 and IL-10 production in this mating combination. These results indicate that the placentally produced anti-inflammatory cytokines can play a vital role in the survival to term of the fetal allograft, by counteracting deleterious inflammatory cytokines.
Flow cytometric analysis for cytokine production identifies T helper 1, T helper 2, and T helper 0 cells within the human CD4+CD27- lymphocyte subpopulation.
Authors: Elson L H , Nutman T B , Metcalfe D D , Prussin C 
Published: December 2022

Abstract
Using three-color flow cytometric analysis for the detection of intracellular cytokines, we have been able to determine the exact combination of cytokines produced by individual T lymphocytes. Because CD4+CD27- lymphocytes have been shown to produce more IL-4 and IL-5 than CD4+CD27+ lymphocytes, cells from normal individuals (n = 4) and helminth-infected patients (n = 4) were sorted magnetically for the CD4+CD27+ and the CD4+CD27- subpopulations. Intracellular staining for IL-4, IL-5, and IFN-gamma subsequent to mitogen stimulation for 6 h revealed that although almost no CD4+CD27- lymphocytes produce both IL-5 and IFN-gamma (0.03-1.4%), a distinct proportion produce both IL-4 and IFN-gamma (0.1-8.0%), and 66% to 84% of IL-5-producing cells also produce IL-4. Patients and normal individuals had the same functional T cell subsets, but the CD4+CD27- lymphocytes from patients had higher frequencies of cells producing IL-4 (geometric mean (GM), 24.3% vs 16.4%) or IL-5 (GM, 10.2% vs 2.9%), whereas those of normal individuals had higher frequencies of cells producing IFN-gamma (GM, 44.5% vs 17.2%; p = 0.043). These analyses also revealed that the CD4+CD27- population included significantly higher frequencies of cells that were IL-5+IFN-gamma- (GM, 4.9% vs 1.5%; p = 0.025), IL-4+IFN-gamma- (GM, 13.8% vs 3.5%; p = 0.025), and IFN-gamma+IL-4-IL-5- (GM, 27.3% vs 12.0%; p = 0.011) than the CD4+CD27+ population. Thus, we have clearly demonstrated Th1, Th2, and Th0 cell subsets within the CD4+-CD27- population of human lymphocytes.
Fas ligand-mediated cytotoxicity is directly responsible for apoptosis of normal CD4+ T cells responding to a bacterial superantigen.
Authors: Ettinger R , Panka D J , Wang J K , Stanger B Z , Ju S T , Marshak-Rothstein A 
Published: December 2022

Abstract
Exposure of naive CD4+ T lymphocytes to superantigens such as staphylococcal enterotoxin B (SEB) induces a strong proliferative response. Prolonged exposure or subsequent restimulation of the responding T cell population with SEB leads to the apoptotic events of activation-induced cell death (AICD). However, T cells derived from either Fas-deficient lpr or Fas ligand-deficient gld autoimmune mouse strains, fail to undergo AICD under these conditions. Instead, these autoimmune T cells mount a vigorous proliferative response, suggesting a critical role for Fas/FasL interactions in this form of autoapoptosis. In the current study, we found that SEB-induced AICD was tied to the rapid induction of FasL expression in cells constitutively expressing high levels of Fas. Furthermore, the addition of soluble Fas-IgG fusion protein to the SEB-restimulated cultures blocked AICD and resulted in a 2 degrees proliferative response that was comparable in magnitude and kinetics to that of the lpr and gld T cells. The rapid onset of apoptosis in normal T cells subsequent to restimulation with SEB was in direct contrast to the proliferative response of the initial cultures, even though comparable levels of Fas and FasL RNA were found in T cells after 1 degree and 2 degrees challenge. The clonal expansion of the normal T cells responding to the initial SEB stimulation was, however, dramatically compromised when the normal cells were cocultured with an MRL-lpr responder population; addition of soluble Fas-IgG rescued the normal component of the response. Together, these data demonstrate first, that Fas/FasL interactions are intimately tied to superantigen-induced AICD, a form of autocrine cell death, and second, that FasL-mediated cytotoxicity is responsible for the disappearance of normal CD4+ T cells in lpr cocultures.
Regulation of L-selectin mRNA in Jurkat cells. Opposing influences of calcium- and protein kinase C-dependent signaling pathways.
Authors: Kaldjian E P , Stoolman L M 
Published: December 2022

Abstract
L-Selectin initiates leukocyte attachment to venular endothelium during lymphocyte recirculation through lymph nodes, leukocyte recruitment into sites of inflammation, and the hematogenous spread of lymphoid malignancies. The density of L-selectin at the cell surface is a major determinant of binding activity and entry into tissues. Post-transcriptional shedding is one control mechanism; however, the extent and physiologic relevance of pre-translational regulation has not been defined. The current study shows that mitogen-/IL-2-driven proliferation of human T cells first increased then markedly decreased the expression of L-selectin on the blast population. The prevalence of specific mRNA showed parallel changes, implying that receptor density is controlled, in part, at the pretranslational level. We used the IL-2-independent Jurkat cell line to determine whether signaling through C-type protein kinases and intracellular calcium regulated L-selectin mRNA directly. Selective pharmacologic activation of these pathways with phorbol esters and calcium ionophore, respectively, resulted in opposite effects on both L-selectin density and mRNA levels. Phorbol esters induced receptor shedding followed by progressive increases in L-selectin density and steady state levels of mRNA. Addition of a calcium ionophore with the phorbol ester blocked both the reexpression of surface receptor and the increase in mRNA. Treatment with ionophore alone resulted in a steady decline in L-selectin expression and mRNA levels. Cyclosporin A, a specific inhibitor of calcineurin, blocked the impact of ionophore on both basal and phorbol-induced levels of L-selectin mRNA. Ionophore alone did not induce apoptosis, significantly alter cell cycle kinetics, or increase transcription of the IL-2 gene under conditions that suppressed L-selectin. Thus, calcineurin seems to be a proximal enzyme in a novel regulatory cascade that suppresses L-selectin expression independent of its known effects on proliferating T cells. In light of the findings in Jurkat, we propose that the protein kinase pathway up-regulates L-selectin mRNA and surface expression early in mitogen-driven T cell proliferation. Chronic elevation of intracellular calcium in repeatedly stimulated T cells then down-regulates expression at the pretranslational level through prolonged activation of calcineurin.
Regulatory role of gamma delta T cells in uterine intraepithelial lymphocytes in maternal antifetal immune response.
Authors: Suzuki T , Hiromatsu K , Ando Y , Okamoto T , Tomoda Y , Yoshikai Y 
Published: December 2022

Abstract
To elucidate the potential roles of the gamma delta T cells in uterine intraepithelial lymphocytes (IEL) in the regulation of maternal antifetal immune response during pregnancy, we examined the kinetics and function of gamma delta T cells in uterine IEL obtained from (C3H/He x AKR/J) pregnancy. The number of gamma delta T cells increased in the uterine IEL in (C3H/HexAKR/J) pregnancy more than those in (C3H/HexC3H/He) pregnancy and much more than in nonpregnant C3H/He mice. The uterine IEL in (C3H/HexC3H/He) pregnancy significantly proliferated in response to AKR/J stimulator cells. In contrast, the uterine IEL in (C3H/HexAKR/J) pregnancy showed little, if any, proliferation in response to the same stimulator cells. gamma delta T cell depletion from the uterine IEL in (C3H/HexAKR/J) pregnancy restored their responsiveness against AKR/J stimulator cells. Both gamma delta T cell-enriched fraction and alpha beta T cell-depleted fraction, but neither gamma delta T cell-depleted fraction nor alpha beta T cell-enriched fraction in the uterine IEL exhibited suppressive activity against allogeneic responses of nonpregnant C3H/He LN cells. This suppressive activity was shown by transferring the supernatant of culture medium in the uterine IEL stimulated with AKR/J cells that contained a large amount of TGF-beta, and the suppressive activity was significantly blocked by addition of anti-TGF-beta mAb to the culture. Taken together, our results suggest that gamma delta T cells in the uterine IEL suppress the maternal antifetal immune response at the maternal-fetal interface at least in part through TGF-beta production to prevent a rejection of the fetus.
Tissue distribution of natural peptides derived from a ubiquitous dehydrogenase, including a novel liver-specific peptide that demonstrates the pronounced specificity of low affinity T cell reactions.
Authors: Wu M X , Tsomides T J , Eisen H N 
Published: December 2022

Abstract
The peptides recognized by CD8+ CTL normally arise by proteolysis of intracellular proteins. To learn whether these peptides are generated similarly in diverse cell types, we examined the variety and abundance of naturally processed peptides that derive from a ubiquitous enzyme, alpha-ketoglutarate dehydrogenase, and are recognized in association with the class I MHC protein, Ld, by a CTL clone (2C). A characteristic set of three peptides was found in diverse tissues, but their abundance varied greatly, apparently unrelated to differences in class I MHC expression, e.g., they were surprisingly abundant in liver. We also found in liver a fourth naturally processed peptide (p2Ca-Y4, LSPYPFDL) that differs by one oxygen atom from a previously characterized natural peptide (p2Ca, LSPFPFDL). CTL discrimination between these peptides in association with the same class I MHC protein, Kb, demonstrates the striking specificity that can be exhibited by low affinity T cell reactions.