bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of bystander inflammatory cytokines on CD8 T cell response to future antigenic encounter. (50.33)
Authors: Thomas Sunil , Kolumam Ganesh , Thompson Lucas , Kaja Murali-Krishna 
Published: January 2023

Abstract
Inflammatory cytokines produced during infection act on a wide variety of cells-these include infected as well as uninfected professional antigen presenting cells, T and B cells. Very few of these cells bear receptors specific to the pathogen derived peptides and a majority are bystander cells. Some of these bystander- activated lymphocytes may potentially encounter cognate antigen at later phases. Here we asked what would be the effect of bystander activation on CD8 T cells if they encountered cognate antigen later. We tested this by subjecting ovalbumin-specific TCR transgenic CD8 T cells (OT-1) to Lymphocytic choriomeningitis virus (LCMV) induced bystander activation in vivo and then assessing their response to ovalbumin. Our results show that prior bystander activation drastically diminishes their ability to expand following cognate antigenic exposure. Further experiments show that Type I interferons, a set of inflammatory cytokines produced predominantly during the early infection are mainly responsible for this inhibitory effect on bystander cells. Paradoxically the action of Type I interferons on T cells around the time of antigenic exposure has a markedly positive effect on clonal expansion. These observations suggest that the behavior of T cells is drastically different depending upon whether they receive inflammatory signals prior to or during TCR encounter, and warrants further studies on effects of inflammation in relation to the time of TCR engagement.
A novel role for Egr-3 in promoting IL-17 producing T cells (50.37)
Authors: Parkinson Rose , Powell Jonathan 
Published: January 2023

Abstract
Our lab has previously shown that anergic CD4+ T cells upregulate the transcription factor Egr-3 and conversely, that overexpression of Egr-3 inhibits a Th1 response and induces anergy. Using a transgenic mouse model of T cell-specific Egr-3 overexpression (Egr-3 Tg), we attempted to induce anergy in Th17 cells and instead made the unexpected finding that Egr-3 Tg T cells produce increased amounts of IL-17 when cultured in non-skewing conditions. Egr-3 Tg Th17 cells coexpress very little IL-10, even when cultured with TGF-b and IL-6. Further examination of these mice revealed that in addition to CD4+ IL-17 producing cells, there was a marked increase double negative IL-17 producing T cells. This prompted us to examine TCR gene usage. Indeed, the IL-17 producing double negative cells, and to a lesser degree CD8+ cells, all employed the γδ TCR. Interestingly, when the Egr-3 Tg mice were bred to CD4+ TCR transgenic mice, the double negative IL-17 producing cells expressed the αβ TCR. These findings suggest that Egr-3 is playing a role in differentiation toward IL-17 producing cells rather than primarily directing γδ T cell differentiation. Overall our findings demonstrate that under different circumstances Egr-3 can act either as a promoter of T cell anergy or a promoter of Th17 differentiation.
The cell-specific induction of CXCL9 by interferon (IFN)-γ in CNS microglia is determined by the myeloid transcription factor PU.1 (51.6)
Authors: Campbell Iain , Carter Sally , Gysbers Vanessa 
Published: January 2023

Abstract
The IFN-γ-inducible chemokines CXCL9 and CXCL10 bind to CXCR3 and are implicated in the pathogenesis of T-cell-mediated immunity in the CNS. However, the cellular localization of these chemokines differs with CXCL9 produced by macrophage/microglia (M/M) while CXCL10 is produced by both M/M and astrocytes. Here we determined the mechanism for the M/M-restricted expression of the Cxcl9 gene induced by IFN-γ. Of a number of transcription factors involved with IFN-γ-mediated gene regulation, PU.1 was present constitutively in murine M/M but not in astrocytes. Both in the brain and in culture, PU.1 was localized exclusively to the nucleus of M/M cells. ChIP analysis revealed that STAT-1, PU.1 and IRF8 were bound to the CXCL9 promoter in IFN-γ-treated M/M, whereas in astrocytes STAT-1 alone bound to the CXCL9 promoter. STAT-1 but not IRF8 was critical for IFN-γ-induced expression of both the Cxcl9 and Cxcl10 genes in M/M and in M/M and astrocytes, respectively. The siRNA-mediated knockdown of PU.1 in M/M markedly impaired IFN-γ induced CXCL9 but not STAT1 or IRF8. D1A astrocyte cells showed partial reprogramming to a myeloid phenotype after transduction with PU.1 with expression of CD11b and acquisition of IFN-γ-induced CXCL9. Thus, while IFN-γ is a pivotal mediator of both Cxcl9 and Cxcl10 gene expression, this cytokine differentially induces the expression of CXCL9 in myeloid cells through a mechanism that is determined by PU.1. Support: NIH NS044905.
2nd generation anti-HIV designer T cells cure HIV-infected cultures and preferentially survive versus 1st generation designer T cells (52.19)
Authors: Selliah Nithianandan , Skowron Gail , Bais Anthony , Gomes Erica , Lu Li , Yang Wen , Junghans Richard 
Published: January 2023

Abstract
Immunotherapies that have the potential to eradicate reservoirs of HIV infected cells may be useful to suppress or cure HIV/AIDS. T cells expressing chimeric immune receptors (CIR) through gene modification (designer T cells) can be redirected to kill HIV-infected cells. Previously, an anti-HIV CIR, CD4ζ (1st generation), was created to kill HIV+ cells. However, the adoptive transfer of autologous CD4ζ T cells failed to control the viral infection in clinical trials. We created a 2nd generation CIR for enhanced potency by providing co-stimulatory signal (CD4CD28ζ). Our data show that both 1st and 2nd generation CIRs expressed well on retrovirally transduced human T cells and kill HIV+ targets with high efficiency, whereas CD28 in the CIR confers a distinct advantage in the expansion potential and cytokine IL2 secretion. Interestingly, our preliminary data show that all 1st generation designer T cells died in 7 days when co-cultured with HIV+ cells, whereas 2nd generation designer T cells survived with cure of the infected cultures. This stunning result shows dramatic benefit in the new 2nd generation CIR versus the 1st generation that was used in human clinical trials. We are presently exploring whether this cell death in the 1st generation designer T cells is due to heightened sensitivity to AICD and/or due to HIV infection. Either way, these data show a striking benefit to our new 2nd generation designer T cells as a promising therapy for HIV/AIDS.
Highly Immunogenic JVRS-100 Adjuvanted Universal Influenza A Vaccine (52.4)
Authors: Callejo Bernadette , Monath Tom , Lay Marla , Chang Stella , Fairman Jeff 
Published: January 2023

Abstract
A vaccine based on a conserved external ectodomain of M2 (M2e) offers the potential for inducing broad-immunity against divergent influenza A strains including pandemic viruses. Cohorts of mice were vaccinated 3x (IM) with M2e in the form of a multiple antigenic peptide with 4 copies of M2e (MAP4), with or without cationic lipid DNA complex adjuvant (JVRS-100). Lethal challenge using different strains of virus (H1N1, H3N2) were done to establish efficacy based on survival. The addition of JVRS-100 to M2e-MAP4 resulted in a significant decrease in morbidity and mortality following lethal challenge with H1N1 (survival 100% vs. 30% without adjuvant) or H3N2 (80% vs. 20%). Adjuvanted vaccine resulted in higher levels of IgG (p=0.0159), IgG1 (p&lt;0.02) and IgG2a (p&lt;0.005) vs. M2e-MAP4 alone. A dose titration of M2e-MAP4 inoculated with a constant amount of JVRS-100 resulted in 100% survival after challenge even at a vaccine dose of 25ng. Addition of M2e-MAP4/JVRS-100 to trivalent inactivated influenza vaccine (TIV) confers full protection with a single vaccination prior to lethal challenge. Competitive binding ELISA confirmed that the sera from vaccinated mice contained M2e conformational epitopes. Vaccination with MAP2 and MAP4 indicated the protective epitopes were dependent on dimeric and not tetrameric configuration of the MAP construct. The experiments demonstrate the potency of MAP configured M2e peptide with the JVRS-100 adjuvant in the development of universal flu vaccine.
Reduced IL-4 production by murine T cells after B cell depletion (83.10)
Authors: Li Yongmei , Dunn Robert , Cohen Philip 
Published: January 2023

Abstract
Anti-mouse CD20 antibody, clone 18B12, depletes B cell effectively in vivo. Previously, we observed that IgG2a-18B12, but not the IgG1 isotype, resulted in partial reduction of CD4+ memory T cells from mice that exhibit Sjogren’ syndrome-like autoimmune disease. To determine the effect of B cell depletion on CD4 T cell function in normal mice, B6 mice were given three weekly i.p. injection of 250 ug each IgG2a-18B12, IgG1-18B12 or control mIgG2a antibodies (n=4 to 5 per group). 14 days after the last injection, both follicular and marginal zone B cells were depleted &gt;99% in IgG2a-18B12 treated group. MZ B cells were reduced by 66% in mice treated with IgG1-18B12. CD4+ T cells were stimulated for 63 hours by plate-bound anti-mouse CD3 and soluble anti-CD28. CD4+ T cells isolated from IgG2a-18B12 treated mice produced levels of IL-2 and IFN-gamma similar to cells from control IgG2a treated mice, but showed 75% reduction in IL-4 production (p=0.014). CD4+ T cells from IgG1-18B12 treated mice showed similar level of IL-4 production as compared to control IgG2a treated group. These findings suggest that in vivo B cell depletion can result in alteration of T cell cytokine production and this effect seems to depend on the isotype of B-cell targeting antibody.
The Role of Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) in Experimental Autoimmune Encephalomyelitis (EAE) (83.20)
Authors: Chang Rhoda , Miller Stephen , Longnecker Richard 
Published: January 2023

Abstract
Multiple Sclerosis (MS) is an inflammatory, autoimmune disease of the central nervous system. The cause of MS is still unknown but epidemiological and immunological studies have implicated Epstein-Barr Virus (EBV), which infects B cells, as a possible etiological agent. Of particular interest is EBV Latent Membrane Protein 2A (LMP2A). Previous work in our lab using transgenic mice in which B cells express receptors for Hen Egg Lysozyme (BCRHEL) and LMP2A has demonstrated that LMP2A enhances the expansion and differentiation of B cells upon immunization with HEL, revealing a potential contribution of LMP2A in autoimmunity. As B cells may be a key player in MS, we wanted to examine the role of LMP2A in the animal model Experimental Autoimmune Encephalomyelitis (EAE). Recombinant MOG protein was immunized into transgenic mice in which B cells express LMP2A. LMP2A mice show increased severity and incidence of disease, and faster onset of disease. LMP2A also affects lymphocyte recruitment into the CNS and enhances activation of lymphocytes in immunized mice. Further in vitro analysis will address the role of LMP2A in lymphocyte activation and antigen presentation.
Ag Specific T Effector (TE), Ag specific Foxp3+ regulatory T cells (Treg), and immune complex (IC) interact in a special testicular microenvironment and promote disease progression in a new spontaneous autoimmune orchitis (EAO) model. (83.25)
Authors: Tung Kenneth , Paul Alberta , Qiao Hui , Grafer Connie , Li Jonathan , Pramoonjago Patcharin , Sparks Josh , Bui Elise , Sun Wei 
Published: January 2023

Abstract
BALB/c mice expressing spermatid-specific transgenic ovalbumin (OVA), when crossed to DO11.10 mice, develop spontaneous EAO that begins at 8 wks, which progresses from preclinical stage (8-16 wks) to clinical stage with infertility (&gt;17 wks). Progression time can be reduced to 3 wks by day 3-thymectomy. In preclinical EAO, DC, TE, Treg and OVA-IC are co-localized in, and confined to, discrete non-invasive cell clusters outside the blood-testis barrier (BTB). In clinical EAO, while remaining confined to the clusters, cells become invasive, penetrate the BTB, and deplete germ cells. Why does EAO progress despite persistent expansion and co-localization of activated Ag specific Treg and TE? To address this conundrum, we have accrued the following findings: 1) Changes in the intrinsic TE function: IFNγ-dominance in preclinical EAO versus IL17-dominance in clinical EAO; and adoptively, preclinical T cells transfer preclinical EAO while clinical T cells transfer clinical EAO; 2) only the TE from clinical EAO resist suppression by Treg, 3) In vivo conversion of Treg to Th1 or Th17 TE occurs in testes with clinical EAO; and 4) Infusion of OVA autoAb rapidly results in new IC deposition in the cell clusters, and promotes EAO progression. We conclude that intra-testicular events, within testis cell clusters, critically modify intrinsic properties of both TE and Treg, with the net effect strongly favoring EAO progression. This may depend on activation by co-localized IC.
Cytokine priming enables triggering of autoreactive CD8 T lymphocytes by low affinity TCR ligands (83.7)
Authors: Ilangumaran Subburaj , Dubois Stephanie , Chen Xi Lin , Leblanc Chantal , Ohashi Pamela , Ramanathan Sheela 
Published: January 2023

Abstract
The cellular and molecular events preceding the initial activation of autoreactive CD8 T cells in several autoimmune diseases remain unclear. Recent reports have implicated IL-6, IL-21, IL-15 and IL-7 in the triggering of autoreactive CD8 T cells in mouse models of autoimmune diseases. We have shown that IL-21 and IL-6 synergize with IL-7 or IL-15 to induce antigen-independent proliferation of naive CD8 T cells, with a concomitant increase in antigen responsiveness. We postulated that the cytokine-induced augmentation of TCR sensitivity (referred herein as ‘cytokine priming’) might enable stimulation of potentially autoreactive CD8 T cells by low affinity self antigens. Here, we show that cytokine priming enables naive TCR transgenic CD8 T cells to respond to low affinity TCR ligands, resulting in proliferation and acquisition of effector functions. We have used a transgenic mouse model of autoimmune type 1 diabetes to show that cytokine-primed autoreactive CD8 T cells acquire the capacity to cause disease following stimulation with weak TCR agonists, and that the diabetogenic potential of these cells is dependent on the continuous availability of IL-15. These findings demonstrate a novel mechanism by which cytokines contribute to the triggering of autoreactive CD8 T cells and have important implications for autoimmune diseases associated with infections and chronic inflammation.
Intrinsic defects in B cell response to influenza vaccination in elderly humans (84.11)
Authors: Blomberg Bonnie , Diaz Alain , Romero Maria , Landin Ana Marie , Frasca Daniela 
Published: January 2023

Abstract
We have previously shown that elderly humans have fewer percentages of CD19+ total B cells, switch memory B cells, and increased percentages of naïve B cells. Activated CD19+ B cells have less E47, AID and Igγ1 circle transcripts (CTs) with age. AID is critical for class switch recombination (CSR) and somatic hypermutation, both necessary for optimal function of immunoglobulin (Ig). More recently we have initiated a series of experiments to measure the antibody response to influenza vaccination by hemagglutination inhibition assay (HI) and associated this with the isolated/intrinsic B cell response to these antigens (containing adjuvants) in vitro. Our results show that the specific in vitro AID response of B cells to vaccination and the in vivo serum HI response to vaccination are both decreased with age. We are currently pursuing these studies with more subjects and with both seasonal as well as H1N1 vaccine response. These results indicate that these biomarkers (decreased E47, AID, CSR, IgG) could more accurately track optimal immune responses and activity, and would be better predictors of vaccine and therapeutic agent effectiveness in humans.
Treg and rapamycin effects on humoral immunity in young and old mice (84.12)
Authors: Benavides Adriana , Fernandez Elizabeth , Sharp Z. , Strong Randy , Kraig Ellen 
Published: January 2023

Abstract
Recently, the mTOR inhibitor rapamycin was shown to extend lifespan in mice even when administered at 20 months of age (Harrison et al. Nature 2009). Although studies have shown that it enhances vaccine efficacy and immune memory, others demonstrated an increase in Tregs and a depression of T cell proliferation. Thus, to assess the effect of rapamycin on humoral immunity, young and old mice were fed a rapamycin or control diet and then immunized 3 times with the protein antigen Omp34 from Aggregatibacter actinomycetemcomitans (Aa), a periodontal pathogen. As expected, rapamycin impaired antibody responses to Omp34 in young mice. In older mice, the humoral response was low and not enhanced by the drug. Serum cytokines were also measured and treatment with rapamycin had no effects. In order to address the role of Tregs, mice in each group were given 3 injections of αCD25 (functionally inactivates Tregs) or an isotype control antibody prior to each immunization. However, this treatment did not reverse the effects seen in antibody titers or cytokine levels, suggesting that Tregs alone do not account for the effects seen. After the last immunization, mice were challenged with viable Aa and protection was assessed. Rapamycin had no effect on protection, but surprisingly, antibody production to Aa in older mice was higher in those fed rapamycin. In younger mice, drug treatment had no effect. In conclusion, rapamycin’s effects on immunity should be assessed in old and young mice.
Kinetic and function of c-Rel in naïve B cells (84.4)
Authors: Damdinsuren Bazarragchaa , Grumont Raelene , Zhang Yongqing , Wood William , Becker Kevin , Gerondakis Steve , Sen Ranjan 
Published: January 2023

Abstract
Temporal control of NF-κB activation has been proposed to play an important role in response of cells to NF-κB -inducing stimuli. Our earlier studies found two phases of NF-κB activation in primary B lymphocytes stimulated via the B cell receptor. Phase I NF-κB is induced via the canonical pathway and leads to transient nuclear expression of RelA and c-Rel. Phase II NF-κB activation is mediated by de novo c-Rel gene transcription and translation. We have followed up these observations to determine the function and mechanism of c-Rel during each phase. Using a combination of biochemical, gene expression studies and gene reconstitution studies we propose that c-Rel provides unique survival functions during both phases of NF-κB activation, and supports cell cycle progression in response to CD40 stimulation in phase II. Our studies help to de-convolute functions of c-Rel that are unique from those that are redundant with RelA in B lymphocytes.
A cyclooxygenase-2 (COX-2) pathway promotes expression of activation-induced cytosine deaminase (AID) within replicating human B cells (84.7)
Authors: Mongini Patricia , Lee Hyunjoo , Trott Joshua , Chiorazzi Nicholas 
Published: January 2023

Abstract
Within an inflammatory milieu, B cells specific for autoantigens or microorganisms can develop tertiary lymphoid foci exhibiting AID, downstream class switching, somatic mutation, and occasionally malignant transformation. This study has examined whether COX-2, recently found elevated within cycling human B lymphoblasts, can contribute to the above. We report that after stimulation with surrogate C3dg-bound Ag, IL-4 and BAFF, CFSE-labeled IgM+ human B cells develop clones expressing division-dependent AID, accompanied by elevated levels of mPGES-1 (an inducible prostaglandin E2 (PGE2) synthase), and the PGE2 receptor, EP2. The contemporaneous expression of these proteins was functionally relevant. Thus, COX-2 inhibitors diminished both AID and class switching to IgG. Furthermore, exogenous PGE2, or selective EP2 agonist, increased AID protein. While PGE2 supplementation consistently augmented daughter cell viability and absolute yield of IgG+ progeny, somewhat surprisingly, within cultures showing higher baseline IgG switching, added PGE2 diminished the proportion of IgG+ viable progeny. Available data suggest that while PGE2-augmented AID promotes IgG switching, this process may also lead to greater activation-induced death. Taken together, these novel findings show that during a T cell-independent burst of proliferation, B cells can upregulate both AID and several COX-2 pathway proteins that constitute a positive amplification route for AID expression.
Actions of novel inflammation-resolving lipid mediators on human B cells (84.9)
Authors: Ramon Sesquile , Serhan Charles , Phipps Richard 
Published: January 2023

Abstract
The resolution of inflammation is an active and dynamic process. Newly identified lipid mediators have been recognized as key players during the process of inflammation resolution. These lipid-derived molecules constitute three classes of compounds (lipoxins, resolvins and protectins), all derived from essential fatty acids. New data demonstrates that these lipid mediators regulate aspects of the immune response, including inhibition of neutrophil infiltration, reduction of T cell cytokine production and stimulation of macrophage phagocytic activity. However, their effects on B lymphocytes are unknown. We show for the first time that the novel lipid mediator lipoxin B4 and 17-HDHA increase the ability of normal human B cells to produce IgM and IgG when activated with CpG plus anti-IgM. The two lipid derived molecules along with lipoxin A4 also enhance B cell differentiation, measured by an increased frequency of CD38+ cells. In addition, resolvin D1 and AT-resolvin also increase antibody production in CpG-stimulated B cells. None of the inflammation resolution lipid mediators affect proliferation and are non-toxic to the cells. Increase of plasma cell differentiation and antibody production coincides with the known involvement of pro-resolving mediators during the late stages of inflammation and pathogen clearance.
Repertoire selection and effector functions of neonatal γδ T cells (85.12)
Authors: Cairo Cristiana , Sagnia Bertrand , Cappelli Giulia , Leke Rose , Leke Robert , Colizzi Vittorio , Pauza C. 
Published: January 2023

Abstract
The neonatal T cell repertoire includes a low frequency of Vγ2Vδ2 T cells. This population is poorly reactive to phosphoantigens or aminobisphosphonates, compared to the adult repertoire in blood. The neonatal Vδ2 cell population also shows a reduced proportion of Vγ2-Jγ1.2 rearrangements; this TCR chain combines with the Vδ2 to endow phosphoantigen responsiveness. We are interested in how the neonatal repertoire is selected to produce the dominant Vγ2-Jγ1.2 rearrangement seen in adults. IL-15 did not improve responses to stimulation, but improved survival. Both IL-2 and IL-15 up-regulated NK receptors and perforin production, although IL-2 preferentially down-regulated CD27 expression, that may be linked to the development of cytotoxicity. Curiously, aminobisphosphonate stimulation in a single round selected a Vγ2 repertoire similar to adults. Thus, neonatal γδ T cells found in cord blood are an attractive model for understanding the genesis of cytotoxic T cells lineages.