bluuebunny/crossref_metadata_2025_split huggingface dataset:
IDENTIFICATION OF PRIMORDIAL ORGANIZED LYMPHOID STRUCTURE IN THE SPLEEN OF TELEOST FISH
Authors: Sunyer J. Oriol , Shibasali Yasuhiro , Takizawa Fumio , Yang Ding , Boudinot Pierre , Krasnov Aleksei 
Published: January 2023

Abstract
Induction of adaptive immune responses in higher vertebrate species occur within organized lymphoid structures (e.g. lymph nodes, Peyer’s patches). It has been proposed that such structures emerged throughout evolutionary time with the goal to maximize encounters between antigens, antigens-presenting cells and B-T lymphocytes. Fish lack such structures and thus, it remains unknown how and where antigen-specific immunoglobulin responses are induced in these species. To understand how systemic immune responses are induced in teleost lymphoid organs, Rainbow Trout were immunized with several soluble protein antigens. Overall, our results identified the spleen as the major site for CD4+ T and IgM+ B cell proliferation in systemic lymphoid organs upon immunization. The proliferating splenic IgM+ B cells were frequently observed as clusters in the vicinity of melano-macrophage centers. Moreover, in these areas we observed aggregates of B and T lymphocytes with a loose organized structure reminiscent of the cellular architecture frequently associated with tertiary lymphoid organs. Laser dissection microdissection of these areas enabled us to evaluating the immunoglobulin IgM repertoires within these structures upon immunization. Critically, repertoire analysis identified processes of antigen-specific B cell clonal expansion. In conclusion, these data points to the previously unrecognized existence of primordial semi-organized lymphoid tissue in the spleen of teleost fish in which adaptive IgM immune responses are induced. Our findings provide strong evidence that the induction of antigen-specific immune responses in all bony vertebrates requires the formation of organized or semi-organized lymphoid structures.
Phenotypic and functional characterization of bovine mucosal associated invariant T (MAIT) cells
Authors: HONG SUYEON , McGill Jodi L 
Published: January 2023

Abstract
Mucosal associated invariant T (MAIT) cells are innate-like T cells that are prevalent in the blood and tissues of many mammalian species. MAIT cells recognize small metabolites derived from the riboflavin pathway that are presented by the highly conserved MHC-related protein-1 (MR1). MAIT cells have been described to play a proinflammatory role during several viral and bacterial diseases in humans and in rodent models. While MAIT cells have been described in cattle at the transcriptional level, little is known about the phenotype or function of this population in the bovine during steady-state or disease conditions. Here, using tetramers that bind to the MR1-restriced T cell receptors on MAIT cells, we investigated the frequency and phenotype of MAIT cells in the peripheral blood and bronchoalveolar lavage of healthy calves and animals with respiratory disease. We determined that cattle have 2 subsets of MAIT cells, defined by their expression of CD8; that bovine MAIT cells have the capacity to secrete IFNγ and IL-17 in response to mitogen stimulation; and that the frequency of MAIT cells in the bronchoalveolar lavage increases in the context of respiratory infection, suggesting that MAIT cells may play an important role in host defense in the respiratory tract of cattle.
An animal model of enhanced disease development following respiratory viral infection in children with chronic lung diseases
Authors: Cheon In Su , Son Youngmin , Sun Jie 
Published: January 2023

Abstract
Infants born prematurely often develop chronic lung diseases including bronchopulmonary dysplasia (BPD). BPD is associated with greatly increased host susceptibility and severe disease development following respiratory viral infection. To this end, we have recently established a neonatal hyperoxia model respiratory viral infection in hosts with lung prematurity and BPD. Using this model, we observed that mice exposed with neonatal hyperoxia (80% oxygen, BPD hosts) developed enhanced diseases following influenza virus or respiratory syncytial virus (RSV) infection compared to those of influenza or RSV-infected control mice. We showed that neonatal hyperoxia leaded to modestly enhanced viral replication in the respiratory tract. Using nanostring immune gene profiling and multiplex cytokine analysis, we found that neonatal hyperoxia markedly enhanced immune-associated gene expression and the production of a number of proinflammatory cytokines and chemokines in the airway compared to those of control mice. Neonatal hyperoxia also increased the accumulation of multiple inflammatory innate cell types that were shown to be pathogenic during respiratory viral infections. Importantly, antiviral T, B cells and NK cells were similar in the lungs between infected neonatal hyperoxia-exposed and control mice, which are consistent with the similar viral clearance kinetics in those mice. Thus, we have successfully established a clinically-relevant mouse model of respiratory viral infection in BPD hosts. We expect to further uncover novel insights on the viral pathogenesis and host disease devlopment in this novel model of respiratory viral infection in hosts with chronic lung diseases.
CD4+ T cell memory restoration upon antiretroviral initiation in people living with HIV
Authors: Sponaugle Alexis Thieme , Clutton Genevieve , Iannone Marie , Eron Joseph , Goonetilleke Nilu 
Published: January 2023

Abstract
HIV infection causes a rapid loss of CD4+ T cells that is attributed to both direct cytotoxicity of infected CD4+ T cells and bystander loss due to high immune activation. In addition to the absolute decrease of CD4+ T cells, a significant decrease in both frequency and number of long-lived memory CD4+ T cells is observed in untreated HIV infection. Antiretroviral therapies (ART) now reliably achieve viral control (&lt;50 copies/ml) and significantly restore CD4+ T cell levels in people living with HIV (PLWH) within months of treatment initiation. Similarly, ART restores CD4 T cell memory formation as evidenced by an increase in frequency and number of long-lived memory CD4+ T cells and vaccine-induced immunity. However, to date studies have provided limited data on when and how quickly CD4+ T cell memory is restored upon ART initiation particularly in the days to weeks following ART. A greater understanding of CD4+ T cell memory formation following ART initiation may inform the formation of the HIV latent reservoir, the majority of which is harbored in long-lived memory CD4+ T cells. The goal of this study is to characterize in detail CD4 + T cell memory restoration following ART initiation. To do this, we have obtained samples from PLWH during untreated infection, 2, 48 and 96 weeks post ART initiation and used the mass cytometry Maxpar Direct Immune Profiling Assay (Fluidigm) to phenotype these samples. Data to date show that CD4+ T cell memory restoration occurs very rapidly, within 2 weeks of ART initiation.
Maturation State of HIV Infected CD4 T Cells Impacts the Inducible Response of the Latent Viral Reservoir
Authors: Spina Celsa A , Mukim Amey , Deshmukh Savitha , Beliakova-Bethell Nadejda 
Published: January 2023

Abstract
A structured microenvironment is necessary for proper immune cell function. While it is rarely possible to use ex vivo experimental models of human tissue (e.g. tonsil), culture of multiple immune cell types together in close contact may benefit cell survival and function. To study HIV latency in primary CD4 T cells, we use an in vitro model, which produces an infected cell hierarchy closely resembling that found in vivo: HIV frequency in effector memory (TEM) &gt; central memory (TCM) &gt; naïve (TN) cells.
To enable mechanistic investigations, we developed a method to track CD4 cell phenotype origins following long-term culture and T cell receptor (TCR) stimulation. TN, TCM and TEM subsets were isolated by sorting and stained with live-cell tracking dyes: carboxyfluorescein (CFSE), Yellow and Violet dye, respectively. The tagged subsets were pooled with unstained CD4 cells to help preserve a healthy microenvironment. This mixture was co-cultured with autologous productively infected, TCR-activated cells to facilitate cell-to-cell HIV transmission and establishment of latency. After 3 days, dye-labeled cells were removed by sorting and rested an additional 3 days to complete provirus integration. Latent HIV reactivation by TCR stimulation was measured with HIV RNA expression by PrimeFlow analysis. Residual dye staining provided inference of initial subset origin on a single cell basis. Using this design improved viability and survival for all maturation subsets, compared to isolating subsets prior to stimulation. Results showed that HIV provirus in TN cells was the most responsive to TCR activation.
In addition, our study highlights a novel approach that can easily be adapted to other rare cell subsets in biologically relevant settings.
CD3 and CD8 coreceptor down-modulation are inversely associated with CD8 T cell functional avidity in humans
Authors: Clutton Genevieve Tyndale , Kallon Sallay , Weideman Ann , Xu Yinyan , Warren Joanna , Council Olivia , Alzhanov Damir , Thaxton Hannah , Hudgens Michael , Kuruc Joann , Goonetilleke Nilu 
Published: January 2023

Abstract
This study investigated the function of memory CD8 T cells in HIV-infected people durably suppressed on antiretroviral therapy (HIV+ cART). We assessed bulk and virus-specific memory CD8 T cells in HIV+ cART and HIV-seronegative individuals (HIV−) by flow cytometry. We observed a population of CD3+ CD8dim CD14− CD16− (CD8dim) T cells that was expanded as a percentage of total CD8 T cells in both HIV− and CMV-seropositive individuals. Bulk memory CD8dim T cells expressed significantly higher CD69 and less MHC Class I and CD127 ex vivo than CD8bright T cells, suggesting recent activation. CD8dim T cells expressed less GLUT1 and PGC-1α and took up less glucose (2-NBDG) and lipid (Bodipy) than CD8bright T cells, indicating relatively lower metabolic activity. Multimer reactivity was used to examine CMV-, EBV- and HIV-specific CD8 T cells ex vivo. Virus-specific populations were consistently CD8high. However, after peptide stimulation, antigen-specific CD8 T cells down-regulated CD3 and CD8. CMV-specific CD8 T cells down-regulated CD3 and CD8 more than HIV-specific cells. CD3 and CD8 downregulation were strongly correlated with the functional avidity of the response. A strong correlation between GLUT1 down-regulation and CD8 down-regulation was also observed, suggesting an association between CD8 expression and metabolic activity. These results suggest that the expanded CD8dim population in HIV+ cART individuals, who are &gt;90% CMV-seropositive, may be driven by ongoing activation of high-avidity CMV-specific CD8 T cells. They also suggest that different virus-specific CD8 T cell populations differentially downregulate components of the TCR complex and metabolism after antigen stimulation, possibly to avoid excessive activation.
Memory CD8 T cell responses are impaired during Zika virus infection in mice
Authors: Valentine Kristen M , Alves Rúbens , Wang Ying-Ting , Shresta Sujan 
Published: January 2023

Abstract
Nearly half the world’s population is at risk for infection by Zika virus (ZIKV), the causative agent of congenital Zika syndrome in infants and Guillain-Barre syndrome in adults. ZIKV vaccination strategies are currently focused on neutralizing antibody (Ab) generation, yet recent evidence suggests that Abs may contribute to pathogenesis under certain conditions. In contrast, increasing evidence supports a key role for T cells in protecting against ZIKV. We have begun to evaluate the generation of memory T cell responses to ZIKV infection in unmanipulated immunocompetent mice. Four-week-old wild-type C57BL/6 mice were infected with ZIKV for 30 days, followed by challenge with ZIKV and evaluation of memory CD4 and CD8 T cell responses at day 3 after secondary ZIKV infection. As expected, total numbers of CD4 and CD8 T cells expanded during secondary ZIKV challenge when compared to primary ZIKV responses at 7 days post-infection. However, only antigen-experienced CD4 T cells (CD11a+CD49d+) and not antigen-experienced CD8 T cells (CD11a+CD8lo) were similarly expanded in secondary infection. These CD8 T cell responses were comprised of short-lived effector cells and not memory precursors, indicating that CD8 T cells memory responses are impaired after primary ZIKV infection. These data suggest potential mechanisms of immune-evasion by ZIKV, and ongoing studies are focused on defining the mechanisms by which ZIKV inhibits the generation of memory CD8 T cell responses. Our findings should offer new strategies for developing ZIKV vaccines that enhance protective T cell responses and avoid pathogenic Ab responses.
Diverse CD8 T cell responses to infection revealed by the collaborative cross
Authors: Martin Matthew D , Sompallae Ramakrishna , Winborn Christina , Harty John T , Badovinac Vladimir P 
Published: January 2023

Abstract
Enhanced host protection against re-infection requires generation of memory T cells of sufficient quantity and functional quality. Unlike well-studied inbred mice, T cell responses of diverse size and quality are generated following infection of humans and outbred mice. Thus, additional models are needed that more accurately reflect variation in immune outcomes in genetically diverse populations and to uncover underlying genetic causes. The Collaborative Cross (CC), a large recombinant inbred panel of mice, is an ideal model in this pursuit due to the high degree of genetic variation present and because it allows for assessment of genetic factors underlying unique phenotypes. The objectives of this study were to determine if the CC models diversity of immune outcomes seen in the human population, and if it could be used to identify genetic factors contributing to the generation of qualitatively and quantitatively distinct memory CD8 T cells. To this end, we analyzed the T cell response following acute LCMV Armstrong infection in 47 strains of CC mice. We found variability in resting immune cell composition and adaptive immune responses generated among CC strains in response to infection and reveal quantitative trait loci and candidate genes responsible for generation of CD62L+ memory CD8 T cells. Our results support the use of the CC to model diversity in immune responses observed in genetically diverse organisms and to uncover regulatory networks and host genetic factors underlying diverse immune outcomes following infection. This study and future studies utilizing the CC have the potential to improve translational efforts for the generation of protective immune responses against cancer and infections of global importance.
NK cells provide DC-mediated ‘help’ in cellular immunity to HIV
Authors: Anderko Renee R. , Rinaldo Charles R. , Mailliard Robbie B. 
Published: January 2023

Abstract
Natural killer (NK) cells are uniquely positioned to positively impact antiviral immunity to HIV-1 due to the pleiotropic nature of their effector functions, including the ability to respond directly to infected cells and to translate environmental cues into functional ‘help’ for other immune cells. In particular, their interplay with dendritic cells (DCs) is powerful in shaping the quality and character of the adaptive immune response. In this study, we explored the ‘helper’ function of NK cells in response to both innate and adaptive stimuli in chronic HIV-1 infection. Freshly isolated NK cells from virally suppressed HIV-1 seropositive individuals were co-cultured for 48h with autologous monocyte-derived immature DCs in the presence or absence of innate stimuli or opsonized target cells. Responding NK cells were assessed for their ability to produce DC-modulating cytokines; DCs harvested from the co-cultures were analyzed for their expression of maturation-associated surface markers, as well as their subsequent ability to produce IL-12p70 and to drive type 1 immunity. DC-derived co-stimulatory factors efficiently activated the ‘helper’ function of NK cells as evidenced by their robust production of IFNγ. Opsonizing antibodies also synergized with IFNα to promote NK ‘helper’ cell activity. Furthermore, interactions between NK cells and DCs induced the development of mature DCs with a heightened ability to produce IL-12p70 and to drive the development of Th1 and cytotoxic T cell responses. Our data demonstrate the capacity of NK cells to enhance DC-mediated immune responses to HIV-1 and, thus, highlight the potential for harnessing the reciprocal crosstalk between NK cells and DCs in the design of novel anti-HIV-1 therapies.
A Statistical Study of the Relative Goodness of Fit of the Two Proposed Theories of Human Blood Group Inheritance
Authors: Strandskov H. H. 
Published: January 2023

Summary
The two genetic theories that have been proposed as an explanation of the inheritance of human blood groups, are outlined. Frequencies expected on the basis of the two proposed theories are calculated for 67 large populations. Pearson's x2 test is applied to the observed and calculated frequencies. Of the 67 populations tested more than 70 per cent are in good agreement with the theory of triple allelomorphs; less than 3 per cent agree as well with the two-factor hypothesis. Of the 49 populations that agree with the one or the other proposed theory 48 or 97 per cent agree better with the theory of triple allelomorphs. The conclusion is reached that the theory of triple allelomorphs explains better the inheritance of human blood groups than does the two-factor hypothesis of von Dungern and Hirzfeld whether or not the latter is complicated by linkage.
Parenteral Denaturization of Foreign Proteins
Authors: Sox Harold C. , Azevedo J. L. , Manwaring W. H. 
Published: January 2023

Abstract
In earlier papers of this series (1, 2) it was shown that intravenously injected horse proteins are apparently retained very nearly quantitatively in the normal canine circulation for about six days, but that by the end of this period of time they are so completely denatured as to be without demonstrable anaphylactic antigenicity for dogs. They still retain, however, part of their original antigenicity for guinea pigs (3).
These observations led us to the tentative conclusion that some at least of the intravenously injected horse proteins are presumably converted into proteins of quasi-canine specificity, conceivably into proteins intermediary in specificity between those of their animal of origin and their new host.
The present paper gives additional evidence in support of this postulate, together with an outline of the subsequent history of these hypothetical quasi-caninized horse protein.
Technic. On account of repeated distemper-like infections during the winter months, winter dogs are ill-suited for quantitative serological work.
Antibodies Against Vaccinia Virus Demonstrable in Vitro
Authors: Thompson Richard , Hazen Elizabeth Lee , Buchbinder Leon 
Published: January 2023

Summary
Sera from rabbits hyperimmunized by intravenous and intraperitoneal injections of vaccinial virus tissues (brain, testicle and skin) caused fixation of alexin in the presence of a suitable dilution of vaccinial brain or skin suspension but not in the presence of non-vaccinial tissue suspensions.
The evidence indicates that this fixation is a process specific for vaccinial virus tissue, regardless of the tissue in which the virus is propagated and that it is not due to the immune reactions of concomitant bacteria.
Studies on the Viscosity of Sensitized Erythrocyte Suspensions
Authors: Went Stephen , Lissak Coloman 
Published: January 2023

Abstract
According to the present state of our knowledge, the alterations produced by agglutinins on bacteria and other cells may occur in quite different ways. It is possible (1) that the agglutinin reduces or neutralizes the electric charge of the cells; (2) that the agglutinin alters the cells by decomposing the protective membranes by which they are held in suspension, or by dehydrating the cellproteins, so that they behave like unprotected inorganic suspensions and are readily precipitated by salts and other electrolytes; (3) that the agglutinin increases the force of attraction between the cells (this force is supposedly exerted by the surface tension of the cells and is termed by Northrop and DeKruif as “cohesive force”). This is in short the present state of the problem we are dealing with as it was developed by a great number of investigators, among them Bechhold (1), Bordet (2), Field and Teague (3), Mansfield (4), Tulloch (5), etc., and particularly by Northrop and DeKruif (6).
Antigenic Analysis of Variants of B. Paradysenteriae and the Serological Relation of One Variant to B. Morgani
Authors: Mackenzie G. M. , Batt Louise N. 
Published: January 2023

Abstract
In a preceding paper (1) the results of a study of the antigenic relationships of five cultures of B. paradysenteriae (Eberthella paradysenteriae) and 4 cultures of B. Morgani (Salmonella Morgani) were described. These cultures were obtained from the stools of ten children involved in a small outbreak of summer diarrhea. The evidence presented in our preceding paper indicated only slight antigenic kinship between the two groups. The overlapping was confined to the group components of the antigenic complex. The present paper describes the results of a study of the antigenic relationships of 2 stable variants which were produced by growing a single cell culture of B. paradysenteriae in homologous immune rabbit serum. Inasmuch as the 5 cultures of B. paradysenteriae isolated during the epidemic of summer diarrhea were found to be serologically identical, only one culture from this group was used in the experimental production of variants.
Attempts to Produce General or Local Hypersensitivity to Vaccinia Virus in Guinea Pigs Actively or Passively Immunized
Authors: Buchbinder Leon 
Published: January 2023

Abstract
The literature relating to the production of specific antibodies in the various virus diseases has been unusually contradictory. However, the trend of current research would seem to indicate that the various antibodies which may be demonstrated as the result of simple infection or hyperimmunization with bacterial antigens can be duplicated with most viruses. Regardless of the cumulative evidence presented in recent years, it cannot be denied that there are obstacles which undoubtedly hinder the demonstration of serological reactivity with antivirus serums in a manner unknown with antibacterial immune serums. The intracellular habitat of viruses has probably been one of the reasons for the lack of similarity and uniformity in the results since in almost all immunological tests these causative agents have not yet been satisfactorily divorced from the animal or plant tissues in which they are propagated.
Studies on Antibodies
Authors: Falk K. George , McGuire Grace , Rosenstein Carolyn 
Published: January 2023

Summary
Antimeningococcus serums were dried by the method previously used with antipneumococcus serums. Solutions of the dried materials made up a short time after the drying gave practically the same antibody content by agglutination tests as the original materials. As with the dried antipneumococcus serums, the agglutinating titers of solutions of dried antimeningococcus serums kept at room temperatures for longer periods of time were greatly diminished. The possible relation of agglutination results to clinical efficacy was discussed. The change in solubility of dried preparations on standing for longer periods of time and the significance of insolubility and inactivation of antibody preparations in this connection were considered briefly.