bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human tumor-infiltrating CD4+ T cells react to B cell lines expressing heat shock protein 70.
Authors: Yoshino I , Goedegebuure P S , Peoples G E , Lee K Y , Eberlein T J 
Published: December 2022

Abstract
Human tumor-infiltrating lymphocytes (TIL) include a minor population of tumor-specific T cells, but the nature of the majority of TIL remains unknown. Recently, it has been suggested that T cells that recognize stressed cells may play an important role in immune surveillance. We have examined the proliferative response of anti-CD3-activated TIL cultures from human tumors against heat-stressed (hs) (42.8 degrees C, 25 min) B cell lines (TK6 (HLA-DR7+, -DRw13+, -DRw52+, and -DRw53+) and JY (HLA-DR4+ and -DRw52+)) and the mutant cell line (T2 (no HLA-DR)) by measuring [3H]thymidine incorporation. TIL lines from three of four ovarian cancers, two of four lung cancers, one of two renal cell cancers, one of two melanomas, and one of one breast cancer showed a positive proliferative response against hs-TK6 and/or hs-JY, but not against hs-T2. These TIL did not respond to autologous tumor cells. The response to hs-B cells was mediated by CD4+ TIL and inhibited by anti-HLA-DR Ab, but not by anti-HLA class I. Protein analysis revealed a significant increase of heat shock protein 70 (hsp70) expression in hs-TK6 and hs-JY. In addition, the CD4+ TIL responded to TK6 that had been pulsed with hsp70. This response could be blocked by anti-HLA-DR Ab. The CD4+ TIL produced IFN-gamma, but not IL-4, in response to hs-TK6. From these results, we conclude that hsp70-reactive CD4+ T cells exist in tumor tissues. Furthermore, these TIL recognize stressed cells and seem to play a Th1-like role that may support antitumor T cell responses at local tumor sites.
Development of C5a receptor antagonists. Differential loss of functional responses.
Authors: Konteatis Z D , Siciliano S J , Van Riper G , Molineaux C J , Pandya S , Fischer P , Rosen H , Mumford R A , Springer M S 
Published: December 2022

Abstract
C5a is a 74-amino acid glycoprotein generated on activation of the C system. The responses evoked by C5a, both in vitro and in vivo, and its association with inflammatory diseases, suggest that a receptor antagonist would be of considerable therapeutic importance. However, efforts at generating antagonists have so far been unsuccessful. Structure/activity studies of the C terminus of C5a have generated peptide analogues with nanomolar affinities, but all of these retain strong agonist properties. We now report hexapeptides of the form NMePhe-Lys-Pro-dCha-X-dArg in which increasing aromaticity at position 5 leads to a progressive loss of agonism with little change in binding affinity. The different responses induced by C5a are lost in the order: degranulation before Ca(2+)-flux before chemotaxis. We also describe the first full antagonist of C5a, because the peptide in which x = Trp is not only devoid of all agonist properties, but it inhibits C5a induced degranulation and C5a stimulated G protein activation.
Ig gamma 2b transgenes promote B cell development but alternate developmental pathways appear to function in different transgenic lines.
Authors: Kenny J J , Stall A M , Fisher R T , Derby E , Yang M C , Tucker P W , Longo D L 
Published: December 2022

Abstract
Analysis of B cell development in three strains of gamma 2b transgenic mice shows that the gamma 2b H chain can replace the microH chain in promoting B cell differentiation. The 348C line produces 90% gamma 2b-only B cells and 10% B cells; which co-express gamma 2b and endogenous sIgM and sIgD. These IgG2b+ B cells develop into mature, recirculating CD23+ B cells. The 343-1 and gamma 2b-T15 transgenic mice produce sIgMhigh:sIgDlow:CD23- B cells that generally co-express the gamma 2b transgene-encoded H chain. Such B cells are either developmentally arrested immature B cells or arise from B-1 (CD5) progenitors. The gamma 2b-T15 mice can produce gamma 2b-only CD23+ B cells following inactivation of the endogenous mu locus, whereas 343-1 mice fail to develop B cells. Thus, gamma 2b H chains: 1) can act alone to promote the development of mature B cells, 2) synergize with microH chains for allelic exclusion, and 3) vary in their influence on B cell development in different transgenic mouse strains.
Regulation of early T cell development by the engagement of TCR-beta complex expressed on fetal thymocytes from TCR-beta-transgenic scid mice.
Authors: Takahama Y , Sugaya K , Tsuda S , Hasegawa T , Hashimoto Y 
Published: December 2022

Abstract
Transgenic expression of the beta-chain of T cell antigen-receptor (TCR) is known to induce the generation of CD4+ CD8+ thymocytes in the immunodeficient scid mouse, in which thymocyte development is otherwise arrested at CD4- CD8- cells. It is not clear, however, whether or not the thymocyte development is controlled by ligand engagement of the TCR-beta complex on the cell surface. In the present study, we have examined how the engagement by Ab of the TCR-beta complex expressed on the TCR-beta-transgenic scid fetal thymocytes can regulate the generation of CD4+ CD8+ thymocytes. Organ cultures of CD4- CD8- day 14 fetal thymocytes from the TCR-beta-transgenic scid mice resulted in the generation of CD4- CD8+ and then CD4+ CD8+ cells. The initial step from CD40- CD8- cells to CD4- CD8+ cells was enhanced by the addition of anti-TCR-beta Ab, whereas the subsequent step from CD4- CD8+ cells to CD4+ CD8+ cells was markedly inhibited by anti-TCR-beta Ab. These results indicate that ligand engagement of the TCR-beta complex can positively and negatively regulate the early thymocyte development. Moreover, the finding that engagement of TCR-beta complex inhibits the generation of CD4+ CD8+ cells suggests that the induction of CD4+ CD8+ thymocytes by the TCR-beta transgene is not an immediate consequence of cell-surface engagement of the TCR-beta complex but requires liberation from the continued TCR-beta signaling.
Alveolar macrophages as accessory cells for human gamma delta T cells activated by Mycobacterium tuberculosis.
Authors: Balaji K N , Schwander S K , Rich E A , Boom W H 
Published: December 2022

Abstract
Alveolar macrophages form the first line of defense against inhaled droplets containing Mycobacterium tuberculosis by controlling mycobacterial growth and regulating T cell responses. CD4+ and gamma delta T cells, two major T cell subsets activated by M. tuberculosis, require accessory cells for activation. However, the ability of alveolar macrophages to function as accessory cells for T cell activation remains controversial. We sought to determine the ability of alveolar macrophages to serve as accessory cells for resting (HLA-DR-, IL-2R-) and activated (HLA-DR+, IL-2R+) gamma delta T cells in response to M. tuberculosis and its Ag, and to compare accessory cell function for gamma delta T cells of alveolar macrophages and blood monocytes obtained from the same donor. Alveolar macrophages were found to serve as accessory cells for both resting and activated gamma delta T cells in response to M. tuberculosis Ag. At high alveolar macrophage to T cell ratios (&gt; 3:1), however, expansion of resting gamma delta T cells was inhibited by alveolar macrophages. The inhibition of resting gamma delta T cells by alveolar macrophages was dose-dependent, required their presence during the first 24 h, and was partially overcome by IL-2. Alveolar macrophages did not inhibit activated gamma delta T cells even at high accessory cell to T cell ratios, and alveolar macrophages functioned as well as monocytes as accessory cells. Monocytes were not inhibitory for either resting or activated gamma delta T cells. These findings support the following model. In the normal alveolus the alveolar macrophage to T cell ratio is &gt; or = 9:1, and therefore the threshold for resting gamma delta T cell activation is likely to be high. Once a nonspecific inflammatory response occurs, such as after invasion by M. tuberculosis, this ratio is altered, favoring gamma delta T cell activation by alveolar macrophages.
Cytokine function during mycobacterial and schistosomal antigen-induced pulmonary granuloma formation. Local and regional participation of IFN-gamma, IL-10, and TNF.
Authors: Chensue S W , Warmington K S , Ruth J H , Lincoln P , Kunkel S L 
Published: December 2022

Abstract
Pulmonary granulomas (GR) with type 1 or type 2 cytokine involvement were induced in presensitized CBA mice by embolization of beads coupled to purified protein derivative (PPD) of Mycobacterium tuberculosis or soluble Ags derived from Schistosoma mansoni eggs (SEA). Using neutralizing Abs against IFN-gamma, IL-10, and TNF-alpha/beta, we examined effects on GR size, GR macrophage function, and regional lymph node (LN) responses. Profoundly different effects were observed in the two models. Anti-IFN decreased PPD-GR size by 20%, but augmented SEA GR by nearly 50%. Anti-TNF abrogated PPD-GR area by 40% and SEA GR by 15% suggesting that TNF contributed more to the former. Anti-IL-10 did not affect GR sizes. Analysis of TNF indicated that IFN was required for maximum production by both PPD GR and SEA GR macrophages. Interestingly, TNF tempered its own expression by SEA GR macrophages. In LN, PPD GR and SEA GR formation was associated with T cell-dependent type 1 (IFN and IL-2) and type 2 (IL-10 and IL-4) cytokine profiles, respectively. In PPD LN, anti-IFN decreased IFN and IL-2 production by 50%. In contrast, anti-IL-10 increased IFN and IL-2 production by two- to fourfold, indicating that IFN and IL-10 had opposing effects on the type 1 response. In SEA LN, anti-IFN decreased IFN production but augmented IL-4 and IL-10 production by 50 and 90%, respectively, supporting the notion that IFN constrains Th2 responses. Conversely, IL-10 promoted the Th2 response. Surprisingly, anti-TNF reduced IL-4 and IL-10 in SEA LN but did not affect PPD LN, suggesting that TNF-alpha or -beta supports Th2 differentiation in LN during the secondary response to schistosomal Ags.
Recruitment and proliferation of CD8+ T cells in respiratory virus infections.
Authors: Tripp R A , Hou S , McMickle A , Houston J , Doherty P C 
Published: December 2022

Abstract
The dramatic increase in the cellularity of the mediastinal lymph nodes (MLN) of mice infected intranasally (i.n.) with influenza viruses is a consequence of both recruitment and proliferation. As many as 20% of the CD8+ subset in the MLN can be shown to be in S or G2 + M phase at 6 days after i.n. challenge with the HKx31 influenza A virus, the percentage of of cycling cells being approximately five times greater for the activated/memory substantial evidence of apoptosis was found for CD8+ T cells recovered from the MLN and lung, particularly at 5 and 7 days after infection. Less than 1/100 of the proliferating T cells could be shown, by limiting dilution analysis (LDA), to be influenza virus-specific CD8+ cytotoxic T lymphocyte precursors (CTLp). A single, low dose (20 mg/kg) of the DNA-targeted drug cyclophosphamide (Cy) caused a massive decrease in frequency for the responding CD8+ CTLp, though the mice survived infection with the HKx31 virus and there was no long-term exhaustion of the CTLp pool in the MLN, spleen, or lung. The Cy treatment was also followed by a smaller reduction in the prevalence of memory CTLp (specific for Sendai virus) that were present concurrently in the regional lymph node, indicating that a measure of bystander activation is occurring. The experiments show that respiratory virus infections have no negative impact on established T cell memory, and that there is no phase of transient exhaustion in the acute virus-specific CTLp response in this localized infection.
The human HIV/peripheral blood lymphocyte (PBL)-SCID mouse. A modified human PBL-SCID model for the study of HIV pathogenesis and therapy.
Authors: Boyle M J , Connors M , Flanigan M E , Geiger S P , Ford H , Baseler M , Adelsberger J , Davey R T , Lane H C 
Published: December 2022

Abstract
PBL from HIV-infected patients were engrafted into CB-17 SCID mice to develop a novel small animal model for the study of HIV pathogenesis and therapy. Engraftment was achieved in 84% of mice, with human Ig (hu-Ig) levels and total human mononuclear cell recovery by peritoneal wash similar to those in control hu-PBL-SCID mice engrafted with uninfected donor cells. The hu-Ig produced by hu-HIV/PBL-SCID mice had broad reactivity against HIV. Virus could be detected in 98% of mice by polymerase chain reaction and/or viral coculture. Viremia was first detected by quantitative polymerase chain reaction on day 7 (approximately 10,000 copies of viral RNA/ml of plasma) and persisted through day 17. Quasispecies analysis of amplified, cloned, proviral DNA of the V3 region of the env gene showed that nucleotide sequences from hu-HIV/PBL-SCID mouse peritoneal wash cells on day 17 were not significantly changed from those derived from donor PBL at the time of injection. Relative to human CD4+ T cell recovery by peritoneal wash in control hu-PBL-SCID mice (CD4 = 19 +/- 2%; n = 40), severe CD4+ lymphocyte depletion (CD4 = 5 +/- 0.5%; n = 59; p &lt; 0.001) was observed in untreated hu-HIV/PBL-SCID mice 18 to 25 days after engraftment. Treatment with 2'-beta-fluoro-2',3'-dideoxyadenosine, a nucleoside analogue, significantly reduced CD4+ T cell depletion (CD4 = 13 +/- 1; n = 59; p &lt; 0.001) and the frequency of virus isolation (70%; p = 0.015) in the hu-HIV/PBL-SCID model. Boosting hu-Ig levels in the mice by injection of purified donor Ig with neutralizing activity did not affect the frequency of CD4+ lymphocyte recovery or virus isolation. The administration of a mAb to TNF had minimal effects. These studies demonstrate that PBL from HIV-infected donors can engraft SCID mice; that HIV can be detected in the spleen, peritoneal wash cells, and blood of these mice; that HIV infection within the model results in rapid CD4+ T cell depletion; and that anti-retroviral therapy is effective in improving CD4+ T cell recovery and reducing the frequency of virus isolation. The hu-HIV/PBL-SCID mouse model thus represents a potentially useful model in which to study HIV pathogenesis and therapy.
Divergent effects of chronic HIV-1 infection on human thymocyte maturation in SCID-hu mice.
Authors: Kollmann T R , Kim A , Pettoello-Mantovani M , Hachamovitch M , Rubinstein A , Goldstein M M , Goldstein H 
Published: December 2022

Abstract
We have recently developed a modified SCID-hu mouse model in which the implanted human thymus and liver (hu-thy/liv) and human peripheral T cells become infected with HIV-1 after i.p. inoculation. By using this model, we evaluated the effect of HIV-1 infection on thymic maturation and observed that different HIV-1 strains had divergent effects of thymic maturation. Although minimal effects on continued thymopoiesis in the hu-thy/liv implant were observed after chronic infection with two primary patient isolates, HIV-1(28) and HIV-1(59), and with HIV-1ADA, HIV-1Ba-L, HIV-1JR-CSF, HIV-1JR-FL, and HIV-1SF162, significant thymocyte depletion was detected after infection with HIV-1IIIB and HIV-1RF. Thus, the effect of HIV-1 infection on thymocyte maturation may depend upon the strain of HIV-1 infecting the thymus. Despite the minimal effects on thymopoiesis observed in the hu-thy/liv implanted in SCID-hu mice 6 mo after infection with HIV-1(28), significant changes were seen in the human T cell population circulating in the peripheral blood of these mice. These changes ranged from an inversion of the CD4/CD8 ratio of peripheral human T cells in some SCID-hu mice to the almost complete depletion of peripheral human T cells observed in other SCID-hu mice. Because these effects were associated with the detection of HIV-1 infection of the peripheral human T cells, these modified SCID-hu mice should prove to be a valuable model for investigating the effects of chronic HIV-1 infection on the peripheral human T cell population.
Decreased CD4-CD8- TCR-alpha beta + cells in lpr/lpr mice lacking beta 2-microglobulin.
Authors: Mixter P F , Russell J Q , Durie F H , Budd R C 
Published: December 2022

Abstract
The CD4-CD8- T cells that accumulate in lpr/lpr mice have previously expressed CD8, on the basis of studies of CD8 alpha gene demethylation. The actual requirement for CD8 interaction with class I MHC molecules to promote the appearance of CD4-CD8- T cells in lpr/lpr mice has also been suggested. To examine this point in more detail, the lpr mutation was bred onto a beta 2-microglobulin-deficient background (beta 2-m-/-). C57BL/6 (B6) mice homozygous for both the lpr mutation of the fas gene and inactivation of the beta 2-m gene (beta 2-m-/- lpr/lpr) develop less alpha beta T cell lymphadenopathy than the parental B6 lpr/lpr strain. This is caused by the near absence of CD8+ T cells and a considerable reduction in CD4-CD8- T cells, revealing an important role for positive selection on class I MHC molecules during the ontogeny of lpr CD4-CD8- T cells. Although absolute numbers of peripheral T cells are decreased in beta 2-m-/- lpr/lpr mice, they manifest a B cell lymphadenopathy with age. beta 2-m-/- lpr/lpr mice display only subtle indications of autoimmune disease with age, compared with parental B6 (beta 2-m+/+)lpr/lpr mice. These include limited histopathologic stages of kidney disease and lack of proteinuria, despite the presence of serum anti-DNA Abs. Thus, absence of class I MHC-positive selection of CD8+ and CD4-CD8- TCR-alpha beta + cells limits the autoimmune diathesis observed in beta 2-m+/+ lpr/lpr mice.
Perturbation of B cell genesis in the bone marrow of pristane-treated mice. Implications for plasmacytoma induction.
Authors: Rico-Vargas S A , Potter M , Osmond D G 
Published: December 2022

Abstract
A single injection of pristane was given i.p. to plasmacytoma-susceptible BALB/cAn mice. At intervals up to 6 mo thereafter, immunofluorescence labeling of intranuclear terminal deoxynucleotidyl transferase (TdT), cell surface B220 glycoprotein, cytoplasmic mu-chains of IgM (c mu), and surface mu-chains (s mu), together with mitotic arrest techniques, were used to quantitate the in vivo population dynamics of precursor B cells in the bone marrow. TdT-expressing pro-B cells (TdT+B220-, TdT+B220+), before the expression of mu-chains, showed sustained increases in both population size and the number of cells flowing through mitosis per unit time. In contrast, populations of pre-B cells (c mu + s mu -) and B cells (s mu +) were consistently depressed for long periods of time, including the phase of plasmacytoma formation. Precursor B cells in DBA/2 mice, a plasmacytoma-resistant strain, showed similar responses to pristane treatment. The results demonstrate that a single injection of pristane, which greatly increases the demand for macrophage activity in the peritoneal space, causes sustained distant alterations in B cell lymphopoiesis in the bone marrow; specifically, a prolonged increased proliferation of pro-B cells coupled with a depression and a exaggerated loss of pre-B cells and B cells. The protracted stress on B cell lymphopoiesis may be a predisposing factor in the subsequent development of c-myc-activating chromosomal rearrangements that play a critical role in plasmacytomagenesis.
Regulatory mechanisms for production of IFN-gamma and TNF by antitumor T cells or macrophages in the tumor-bearing state.
Authors: Yamamoto N , Zou J P , Li X F , Takenaka H , Noda S , Fujii T , Ono S , Kobayashi Y , Mukaida N , Matsushima K 
Published: December 2022

Abstract
Spleen cells from BALB/c mice bearing a syngeneic tumor (CSA1 M) 2 to 3 wk after inoculation with CSA1 M cells produced IL-2, IFN-gamma, and TNF upon in vitro cultures. This was previously demonstrated to be a result of collaboration between tumor-primed CD4+ T cells and APCs binding CSA1 M tumor Ags in vivo. The IL-2- and IFN-gamma-producing capacities decreased with the progress of tumor-bearing stages. This was parallel to the levels of IL-2 and IFN-gamma mRNAs expressed by cultured spleen cells. In contrast, comparable levels of TNF mRNA were expressed by all groups of cultured cells. However, large amounts of TNF were secreted by the cells from early but not from late tumor-bearing mice. TNF was produced mainly by the non-T cell fraction upon stimulation with CD4+ T cell-derived IFN-gamma. Therefore, the reduced TNF production by whole spleen cells from late tumor-bearing mice was restored by addition of rIFN-gamma to their cultures. Reciprocally to the progressive decrease in the production of IFN-gamma/TNF, the capacities of tumor-bearing mice to produce TGF-beta and IL-6 increased along with tumor growth. TGF-beta suppressed production of IL-2, IFN-gamma, and TNF, but not of IL-6. Moreover, IFN-gamma/TNF production was negatively regulated by IL-6. Taken together with the fact that the growth of CSA1 M cells is completely inhibited by the combination of TNF and IFN-gamma, these results demonstrate that the tumor-bearing state induces an abnormal cytokine network under which the production of antitumor cytokines is negatively regulated.
Class II MHC gene expression in microglia. Regulation by the cytokines IFN-gamma, TNF-alpha, and TGF-beta.
Authors: Panek R B , Benveniste E N 
Published: December 2022

Abstract
The molecular mechanism(s) by which three cytokines (IFN-gamma, TNF-alpha, TGF-beta) affect class II MHC gene expression in primary rat microglia was examined. IFN-gamma is a potent inducer of the class II gene, and this induction is unaffected by treatment with either TNF-alpha or TGF-beta. Transient transfection of primary rat microglia with an HLA-DRA promoter linked to the chloramphenicol acetyltransferase reporter gene (DRA-CAT) demonstrated that IFN-gamma acts at the transcriptional level to induce class II MHC gene expression, and that TNF-alpha and TGF-beta have no influence on IFN-gamma-induced promoter activity. Experiments using a series of DRA substitution mutants that individually affect the W, X1, X2, or Y elements, as well as a double mutation in both X1 and X2, indicate that all four of these elements are required for responsiveness of the DRA promoter to IFN-gamma. The effect of IFN-gamma and TNF-alpha on DNA binding proteins by microglia was examined. A constitutive complex with specificity for the X2 box was detected in extracts from unstimulated microglia. IFN-gamma treatment changed this complex to migrate with slower mobility, and TNF-alpha had no effect on either the constitutive or IFN-gamma-induced complexes. These studies provide information on the molecular regulation of the class II MHC gene in microglia, a cell type critically involved in immune regulation within the central nervous system.
IL-4-producing CD8+ T cell clones can provide B cell help.
Authors: Cronin D C , Stack R , Fitch F W 
Published: December 2022

Abstract
Interactions between CD4+ T cells and B cells are mediated by both soluble factors and cell surface molecules. The Ag-independent interaction between the CD40 ligand, expressed on activated T cells, and its CD40 receptor, expressed on B cells, enhances B cell proliferation in response to IL-4 stimulation. The expression of the CD40 ligand is induced on CD4+ T cells by stimulation with Ag-pulsed APC or mitogens. Here, we show that at least some IL-4-producing murine CD8+ T cell clones can be induced to express the CD40 ligand when stimulated with anti-CD3 mAb. Additionally, such activated CD8+ IL-4-producing clones potentiate the proliferative response of small resting B cells to IL-4 and induce Ig secretion by small resting B cells to IL-4 and IL-5. Proliferation of small resting B cells cultured with IL-4 in the presence of activated IL-4-producing CD8+ murine T cell clones appeared to be mediated by the expression of the CD40 ligand on the T cell because an anti-CD40 ligand mAb inhibited this proliferative response. A conventional murine CD8+ CTL clone, which did not produce IL-4 or express CD40 ligand upon activation, did not potentiate proliferation of small resting B cells exposed to IL-4. Thus, under some circumstances, CD8+ T cells that are able to express CD40 ligand may be able to provide B cell help.