bluuebunny/crossref_metadata_2025_split huggingface dataset:
A selective inhibitor of dipeptidyl peptidase I impairs generation of CD8+ T cell cytotoxic effector function.
Authors: Thiele D L , McGuire M J , Lipsky P E 
Published: December 2022

Abstract
CTL express high levels of dipeptidyl peptidase I (DPPI), a granule thiol protease able to convert the zymogen precursors of granzymes A and B into active proteases. In the present studies, the effects of specific inhibition of DPPI on generation of CTL effector functions were examined. When T cell DPPI activity was inhibited by &gt;95% throughout 5-day MLC, a significant reduction in the generation of CD8+ T cell BLT esterase activity (&lt;30% of control) and cytolytic activity (&lt;10% of control) was observed. DPPI inhibition during the second to fourth days of 5-day MLC also was associated with reduced proliferation of CD8+ T cells, but had no effect on CD4+ T cell proliferation or IL-2 production by either population. CTL generated in the continuous presence of DPPI inhibition also exhibited impaired lysis of anuclear erythrocyte targets and diminished killing of nucleated targets by perforin-independent pathways. In contrast, inhibition of DPPI during only the last 24 h of 5-day MLC was associated only with reduced generation of BLT esterase activity and reduced lysis of nucleated targets by perforin-dependent pathways. Repeated or delayed inhibition of DPPI in MLC containing granzyme B-deficient responder cells also impaired generation of cytotoxic activity. These results indicate that DPPI or other DPPI-like protease activities not only are required for the activation of granzymes, but also play a role in the expansion and differentiation of full CD8+ T cell cytolytic activity.
The mouse anaphylatoxin C3a receptor: molecular cloning, genomic organization, and functional expression.
Authors: Tornetta M A , Foley J J , Sarau H M , Ames R S 
Published: December 2022

Abstract
The anaphylatoxin C3a receptor (C3aR) is unique among the family of G protein-coupled receptors in possessing an unusually large predicted second extracellular loop. To isolate the mouse C3aR, a probe derived from this extracellular loop was used to screen a mouse brain cDNA library. A 3.3-kb cDNA encoding an open reading frame of 477 amino acids was identified. The predicted amino acid contained four predicted N-linked glycosylation sites and was 65% identical to the 482 amino acids comprising the coding region of the human C3aR. Northern blot analysis revealed that this gene was expressed in a variety of mouse tissue and was especially abundant in heart and lung tissues. The mouse C3aR cDNA was used as a probe to isolate a mouse C3aR genomic clone. The nucleotide sequence of the mouse C3aR genomic clone was identical to the cDNA throughout the coding region, indicating that the receptor is encoded on a single exon. The C3aR cDNA was subcloned into a mammalian expression vector and transiently expressed in HEK-293 cells. Binding of radiolabeled C3a to the transfected cells was competed in a dose-dependent manner by increasing concentrations of unlabeled C3a, with a 50% inhibiting concentration of 10 nM. Similar to the human C3aR, RBL-2H3 rat basophilic cells stably expressing this receptor responded in a dose-dependent manner to C3a, a synthetic C3a peptide agonist, but not C4a or C5a, with a vigorous calcium mobilization.
Involvement of NK1+ CD4- CD8- alphabeta T cells and endogenous IL-4 in non-MHC-restricted rejection of embryonal carcinoma in genetically resistant mice.
Authors: Nakamura E , Kubota H , Sato M , Sugie T , Yoshida O , Minato N 
Published: December 2022

Abstract
Non-MHC-restricted rejection mechanisms against the murine MHC-negative F9 embryonal carcinoma cells were analyzed. Strains of C57BL/6 (B6) background were resistant to the tumors irrespective of H-2 haplotypes, while others, including BALB/c background, were susceptible. This resistance was suggested to be mediated primarily by the host thymus-dependent alphabeta T cells, since both athymic B6 nude and normal B6 mice depleted with alphabeta T cells showed susceptible phenotype. The difference of the nature of alphabeta T cells infiltrating in H-2-identical B6- and BALB.B-derived tumors was then comparatively analyzed. It was revealed that unique T cells with NK1+ CD4- CD8- (double negative (DN)) alphabeta TCR+ phenotype were accumulated significantly in B6, but few in BALB.B mice. The population freshly isolated from the F9 tumor tissues preferentially expressed potent IL-4 mRNA, and was suggested to be mostly responsible for the endogenous IL-4 production. Indeed, the injection of either anti-NK1.1 or anti-IL-4-neutralizing Ab into the normal B6 rendered them significantly susceptible to the tumor cells. These results strongly suggested that NK1+ DN alphabeta T cells were responsible primarily for the rejection mechanisms against F9 tumors. Histologically, F9 tumors in B6 mice were characterized by abundant macrophage infiltration and massive tumor necrosis, neither of which was observed in those in BALB.B nor B6 mice preinjected with anti-IL-4 Ab, indicating that both histologic features in the resistant strain were dependent on the endogenous IL-4. Present results provide one of the first instances in which a recently emerging minor T cell subpopulation, thymus-dependent NK1+ DN alphabeta T cells, plays an essential role in anti-tumor responses in vivo.
High susceptibility to collagen-induced arthritis in mice lacking IFN-gamma receptors.
Authors: Manoury-Schwartz B , Chiocchia G , Bessis N , Abehsira-Amar O , Batteux F , Muller S , Huang S , Boissier M C , Fournier C 
Published: December 2022

Abstract
Collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis, is induced in DBA/1 (H-2q) mice following immunization with type II collagen (CII) in CFA. Since we have previously shown that IFN-gamma exerts a biphasic effect during the evolution of CIA in DBA/1 mice, we analyzed the development of this disease in mice with a disruption of the IFN-gamma receptor gene (IFN-gammaR(0/0)). Mutant mice were interbred with the DBA/1 strain to yield IFN-gammaR(0/0) mice expressing the H-2q haplotype. In three consecutive experiments, IFN-gammaR(0/0) male mice were found to exhibit severe clinical and histologic arthritis with an average incidence of 88.5 vs 94.1% for the wild DBA/1 strain. Notably, onset of clinical symptoms occurred significantly earlier than in DBA/1 mice. Although of a lower magnitude than in males, CIA also developed early in IFN-gammaR(0/0) female mice and with higher clinical severity than in control DBA/1 females. Immunization of knockout mice with CII resulted in the generation of CII-specific T cells belonging to the Th1 phenotype that recognize the same immunodominant peptides as do DBA/1 mice. CIA in IFN-gammaR(0/0) mice was associated with a down-regulation of the CII-specific IgG response, and this impairment was essentially due to a strong reduction of Abs of the IgG2a isotype. Taken together, our findings provide evidence that IFN-gammaR deficiency in DBA/1 mice leads to the occurrence of severe CIA with an accelerated onset compared with that in wild-type mice, indicating that the proinflammatory action of IFN-gamma has been bypassed in the IFN-gammaR(0/0) mice.
Reduced production of IL-12 and IL-12-dependent IFN-gamma release in patients with allergic asthma.
Authors: van der Pouw Kraan T C , Boeije L C , de Groot E R , Stapel S O , Snijders A , Kapsenberg M L , van der Zee J S , Aarden L A 
Published: December 2022

Abstract
In atopic patients, allergen-specific T cells have acquired the Th2 phenotype, which is considered to be responsible for the class switch to IgE Ab formation. Because IL-12 is a key cytokine for the induction of Th1 responses, a reduced capacity to produce this cytokine could lead to aberrant Th2 development. Therefore, we examined the production of IL-12 in whole blood cultures from patients with allergic asthma (n = 15) in comparison with nonatopic control subjects (n = 15) to different stimuli. After stimulation with Staphylococcus aureus Cowan I strain (SAC) we observed a 2.6-fold reduction of IL-12 p70 production in the patient group (p &lt; 0.005). This was not due to a general failure of monocytes from these patients to produce cytokines, because the production of IL-6 was normal. SAC also induced the production of IFN-gamma, which was blocked by neutralization of IL-12. In line with the reduced levels of IL-12 secretion, the patient group showed a 3-fold reduction of IL-12-dependent IFN-gamma production (p &lt; 0.005). The amounts of IL-12 and IFN-gamma were positively correlated in both the patient (R = 0.51 at 0.05% SAC and R = 0.64 at 0.01% SAC) and the control groups (R = 0.64 at 0.05% SAC and R = 0.70 at 0.01% SAC). The IFN-gamma:IL-12 ratio was not different between patients and control subjects, indicating a normal response to IL-12. Diminished production of IL-12 and IFN-gamma could not be explained by an increased production of IL-10, because in SAC-stimulated cultures IL-10 was hardly induced in both groups. Furthermore, after stimulation with Escherichia coli, the production of IL-10 was similar in patients and control subjects.
Natural killer cell- and macrophage-mediated rejection of concordant xenografts in the absence of T and B cell responses.
Authors: Lin Y , Vandeputte M , Waer M 
Published: December 2022

Abstract
Hyperacute, complement-mediated xenograft (Xg) rejection is a first major hurdle for xenotransplantation. Thereafter, cellular immunity, including T and B lymphocytes, NK cells, and macrophages may become involved as well. In the present study, hamster heart Xgs were performed in Leflunomide (LF)-treated nude rats. These animals, which are genetically T cell deficient, are known to have a strong NK activity. Moreover, xenoantibody (XAb) formation by B lymphocytes was previously shown to be blocked in nude rats by LF. Hence, this model was well suited to study the role of NK cells and macrophages in Xg rejection. Despite a total suppression of XAb formation, LF-treated nude rats rejected hamster heart Xgs at a same speed (3 days) as untreated nude rats. NK cells played a major role in this rejection process. Indeed, an NK cell-dominated cellular infiltration was noticed in the rejected Xgs and the addition of an anti-NK cell serum, anti-Asialo GM-1 (ASGM-1), to the LF treatment resulted in a significant delay of Xg rejection (from 3 days to 6 days; p &lt; 0.0001) that seemed to be mediated by activated macrophages because 1) spleens from rejecting animals showed an increased percentage of macrophages (ED1+ or ED2+) and 2) rejected Xgs were infiltrated predominantly by macrophages. Moreover, splenocytes taken from rats that rejected Xgs despite a treatment with LF + ASGM-1 provoked an acceleration of Xg rejection when transferred to newly transplanted LF + ASGM-1-treated nude rats, and finally, the latter accelerating effect disappeared when macrophages were first depleted from the adoptively transferred splenocytes. This study thus shows that NK cells and macrophages can be activated in the absence of T cells or XAbs to directly reject Xgs.
Involvement of IL-4-producing Vbeta8.2+ CD4+ CD62L- CD45RB- T cells in non-MHC gene-controlled predisposition toward skewing into T helper type-2 immunity in BALB/c mice.
Authors: Nishimura T , Santa K , Yahata T , Sato N , Ohta A , Ohmi Y , Sato T , Hozumi K , Habu S 
Published: December 2022

Abstract
It was found that freshly isolated BALB/c CD4+ T cells produced high levels of IL-4 and IL-10 in response to immobilized anti-CD3 mAb, while C57BL/6 CD4+ T cells produced low amounts of IL-4 and IL-10. The high IL-4-producing ability of BALB/c mice was demonstrated to be genetically dominant and it was controlled by non-MHC gene (or genes). The cells responsible for IL-4 production in BALB/c mice were defined as TCRVbeta8.2+ CD4+ CD62L- CD45RB- memory-type T cells, which were distinct from NK1.1+ CD4+ NKT cells. Although these memory-type T cells were also detected in C57BL/6 mouse spleen at the same frequency, they showed a functionally different property from BALB/c CD4+ CD62L- CD45RB- T cells in terms of IL-4 production. The fact that germfree BALB/c mouse spleen cells also produced high levels of IL-4 suggested that the IL-4 producer in BALB/c mice might be developed under the influence of unknown factors other than environmental Ags. The CD4+ CD62L- CD45RB- T cells obtained from BALB/c mice accelerated the development of IL-4-producing memory-type CD4+ T cells from CD4+ CD62L+ CD45RB+ naive T cells prepared from OVA-specific TCR-transgenic mice. Therefore, IL-4-producing CD4+ CD62L- CD45RB- T cells might play an important role in the preferential induction of Th2-dominant immunity in BALB/c mouse strain.
Regulation of thymocyte lineage commitment by the level of classical protein kinase C activity.
Authors: Ohoka Y , Kuwata T , Asada A , Zhao Y , Mukai M , Iwata M 
Published: December 2022

Abstract
Thymocyte-positive selection involves signaling through TCR and accessory molecules, and the signaling intensity appears to be critical for this event. The specific inhibitor of classical Ca2+-dependent protein kinase C (cPKC), Gö 6976, inhibited positive selection in fetal thymus organ culture, indicating that cPKC activation is essential for positive selection. The major protein kinase C isoforms in CD4+ CD8+ thymocytes are cPKC-alpha, cPKC-beta, and the novel Ca2+-independent protein kinase C, nPKC-epsilon. To analyze the effect of cPKC activation level on positive selection, we used thymocytes from TCR transgenic mice with nonselecting and RAG-2 -/- backgrounds as they were developmentally arrested at the CD4+ CD8+ stage without positive selection signals. These thymocytes survived and acquired CD4/CD8 lineage commitment in suspension culture upon transient stimulation with limited concentrations of the selective activator of cPKC-alpha and -beta, thymeleatoxin, and the calcium ionophore, ionomycin. However, neither 12-deoxyphorbol 13-phenylacetate 20-acetate, which selectively activates cPKC-beta, nor ingenol 3,20-dibenzoate, which selectively activates nPKC-epsilon, exerted such an effect. The thymeleatoxin/ionomycin concentrations corresponded to those that inhibit glucocorticoid-induced apoptosis in thymocytes and were lower than those that induce proliferation of mature T cells. The CD4 lineage commitment required a higher level of cPKC activity than the CD8 lineage commitment. CD8alpha or CD4 mRNA expression was down-regulated. Functional helper and killer T cells were induced from the CD4 and CD8 lineage-committed cells, respectively, by additional stimulation. These results suggest that thymocyte lineage commitment in positive selection is regulated by the level of cPKC-alpha activity or by the levels of cPKC-alpha and -beta activities.
Adoptive transfer of gut intraepithelial lymphocytes protects against murine infection with Toxoplasma gondii.
Authors: Buzoni-Gatel D , Lepage A C , Dimier-Poisson I H , Bout D T , Kasper L H 
Published: December 2022

Abstract
Intraepithelial lymphocytes (IEL) of the gut represent a primary immune barrier against infection by orally acquired pathogens. Naturally acquired infection with Toxoplasma gondii induces the proliferation of CD8+ T cells in both the gut and spleen. Gut-derived CD8alpha/beta+ IEL exhibit MHC-restricted cytotoxicity against parasite-infected enterocytes and macrophages. In a murine model, we demonstrate that the adoptive transfer of IEL obtained from inbred mice at day 11 postinfection is able to protect against a virulent challenge in syngenic recipients. In CBA mice, the parasite cyst load within the brain of the recipients receiving primed IEL was reduced by 90%. In BALB/c and C57BL/6 mice, a 50% decrease in mortality was observed following adoptive transfer of primed IEL. To determine the T cell subset responsible for protective immunity, a purified CD8alpha/beta+ IEL population was isolated from infected mice at day 11 postinfection. These cells were able to protect naive mice by adoptive transfer against a lethal parasite challenge. RNA analysis by reverse-transcriptase PCR revealed that primed CD8alpha/beta+ IEL produce significant message for IFN-gamma, an essential cytokine for host protection against toxoplasmosis. Administration of anti-IFN-gamma at the time of adoptive transfer of primed IEL abrogated protection. The adoptive transfer of these protective IEL was not restricted to the Ld class I locus. These data demonstrate that IFN-gamma-producing IEL may be an important primary barrier against acute and perhaps recurrent infection with T. gondii.
Transendothelial migration of lymphocytes from HIV-1-infected donors: a mechanism for extravascular dissemination of HIV-1.
Authors: Birdsall H H , Trial J , Lin H J , Green D M , Sorrentino G W , Siwak E B , de Jong A L , Rossen R D 
Published: December 2022

Abstract
To identify factors that cause HIV-1 to establish perivascular foci of infected cells, we studied the transendothelial migration of blood mononuclear leukocytes (MNL) from 76 HIV+ patients and 41 controls. The fraction of patients' lymphocytes that migrated across endothelial cell monolayers in vitro was significantly increased (p &lt; or = 0.03) compared with that of control donors. Migration of patients' CD4+ T cells was particularly enhanced, whereas the migration of monocytes did not differ between patients and controls. Lymphocyte migration correlated with expression of CD11a/CD18 and CD49d/CD29 and with the quantity of TNF-alpha produced as MNLs migrated through the endothelium. Measurement of HIV-1 proviral DNA copies in the patients' MNLs (n = 26) suggested that in half the cases virus-infected cells accumulated preferentially amidst the migratory leukocytes. We observed the same behavior with normal donor MNLs infected, in vitro, with each of 4 strains of HIV-1. The number of HIV-1 proviral DNA copies per million MNLs was 40 to 178 times higher in the migratory population than in the original population added to the endothelium. To test whether only certain strains of HIV-1 stimulate transendothelial migration of infected cells, we used single strand conformation polymorphism analysis to identify quasispecies of HIV-1 in the MNLs. If all strains of HIV-1 were equal in their ability to stimulate transendothelial migration, we expected to find no differences in the quasispecies present in the original and migratory cell populations. In fact the quasispecies differed in 14 of 19 paired samples, suggesting that only certain HIV-1 quasispecies promote transendothelial migration of infected cells.
Experimental autoimmune myasthenia gravis in B10.BV8S2 transgenic mice: preferential usage of TCRAV1 gene by lymphocytes responding to acetylcholine receptor.
Authors: Kaul R , Wu B , Goluszko E , Deng C , Dedhia V , Nabozny G H , David C S , Rimm I J , Shenoy M , Haqqi T M , Christadoss P 
Published: December 2022

Abstract
Multiple TCRBV genes have been implicated in experimental autoimmune myasthenia gravis (EAMG) pathogenesis in susceptible H-2(b) strains of mice. We studied the contribution of specific TCRBV and AV genes in EAMG pathogenesis using B10.BV8S2 transgenic mice (H-2[b]). The TCR transgenic mice predominantly have TCRBV8S2 transgene, but can use any of the endogenous AV gene repertoire. The transgenic mice were immunized with acetylcholine receptor (AChR) in CFA and evaluated for EAMG pathogenesis. Although the lymphocyte responses to AChR in B10.BV8S2 transgenic and nontransgenic TCR wild-type mice were equivalent, a marked reduction in lymphocyte response to the dominant AChR alpha chain peptide 146-162 was observed in the TCR transgenic mice. After boosting with AChR in CFA, anti-AChR Abs were detected in the serum, and 14 of 42 (33%) of the TCR transgenic mice developed clinical EAMG. Furthermore, EAMG in TCR transgenic mice was prevented by treatment with mAb to TCRBV8, which depleted BV8-expressing T cells. Cloning and sequencing of TCRAV genes from AChR-reactive T cells from B10.BV8S2 transgenic mice revealed a pattern of restricted TCRAV gene usage. The majority (60%) of the clones sequenced showed a sequence identical with that of the TCRAV1S8 gene. In the normal spleen cells of TCR transgenic mice, AV gene usage was more random. Thus, despite the presence of a complete endogenous TCRAV repertoire in B10.BV8S2 transgenic mice, T cells responding to AChR preferentially used a single endogenous TCRAV gene, thus implicating the involvement of the TCRAV1S8 gene in EAMG pathogenesis.
Functional dissection of systemic lupus erythematosus using congenic mouse strains.
Authors: Morel L , Mohan C , Yu Y , Croker B P , Tian N , Deng A , Wakeland E K 
Published: December 2022

Abstract
We describe the in vivo phenotypes associated with three genomic intervals containing systemic lupus erythematosus (SLE)-susceptibility genes derived from the SLE-prone NZM2410 strain on a C57BL/6 genome. These intervals were identified previously via a genome-wide analysis of SLE susceptibility in a (NZM2410 x C57BL/6)F1 x NZM2410 backcross, and transferred independently on a C57BL/6 background to produce three congenic strains: B6.NZMc1 carrying Sle1, B6.NZMc4 carrying Sle2, and B6.NZMc7 carrying Sle3. B6.NZMc1 develops high titers of IgG anti-nuclear autoantibodies in the absence of any severe nephritis. B6.NZMc4 spontaneously develops elevated levels of IgM, but not IgG Abs against several Ags, indicative of polyclonal activation or polyreactivity affecting the B cell lineage. B6.NZMc7 causes the production of IgM and IgG Abs against both nuclear and non-nuclear Ags and the development of severe lupus nephritis. Therefore, our results show that three defined genomic intervals from the NZM2410 SLE-prone strain each contribute specific component phenotypes that have been associated with SLE, which in combination can mediate severe disease.
Plasmin-induced proteolysis of tenascin-C: modulation by T lymphocyte-derived urokinase-type plasminogen activator and effect on T lymphocyte adhesion, activation, and cell clustering.
Authors: Gundersen D , Trân-Thang C , Sordat B , Mourali F , Rüegg C 
Published: December 2022

Abstract
Proteolysis and remodeling of the extracellular matrix occur physiologically in processes such as tissue morphogenesis and repair and may participate in the regulation of complex cell functions, including proliferation and differentiation. While matrix degradation appears to be relevant to T lymphocyte migration through tissues, little is known about whether degraded matrix affects T lymphocyte function. We have studied the interaction between T lymphocytes and tenascin-C (TN-C), a matrix protein we have previously reported to inhibit T lymphocyte activation, in the context of plasmin-induced degradation. Here we report that plasmin efficiently cleaves TN-C. Peripheral blood T lymphocytes stimulated with phorbol ester, anti-CD28, or anti-CD3 Ab, induce, within 24 to 48 h, a strong plasminogen-dependent proteolysis of TN-C. We demonstrate that stimulated T lymphocytes activate plasminogen by secreting the urokinase-type plasminogen activator (u-PA). Plasminogen activation by T lymphocyte-derived u-PA occurs efficiently in fluid phase in the absence of cells. We investigate the consequences of plasmin-induced proteolysis on three of the effects of TN-C in relation to lymphocyte functions. Plasmin proteolysis converts TN-C from a nonadhesive into an adhesive substrate for T lymphocytes and abolishes its aggregating activity on PBMC. In contrast, the inhibitory effect of TN-C on T lymphocyte activation remains unaffected. These observations demonstrate that stimulated T lymphocytes induce plasminogen-dependent proteolysis of TN-C by secreting u-PA and suggest that proteolysis of TN-C may represent a mechanism by which to regulate some of its effects on T lymphocyte functions.