bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suppression and enhancement of HIV replication in macrophages by CD8+ lymphocytes (105.43)
Authors: Kavanagh Daniel , Rodriguez-Garcia Marta , Levi Karen , Kaufmann Daniel 
Published: January 2023

Abstract
CD8+ cytolytic T cells can suppress HIV replication by a variety of lytic and nonlytic mechanisms, and the relative clinical importance of particular CTL functions is not fully understood. Therefore studies have utilized various in vitro viral suppression assays as an indication of the antiviral efficacy. We measured antiviral activities of CD8+ lymphocytes from elite controllers who spontaneously suppress HIV without medication, from chronically infected HIV+ donors, and from HIVneg donors. Bulk CD8+ lymphocytes containing a CD56+ fraction suppressed HIV replication in autologous macrophages, even for HIVneg donors. CD56-depleted CD8 T cells from HIV+ donors also suppressed HIV replication in macrophage targets, with elite controller T cells exerting significantly greater suppression than progressor T cells. CD56-depleted CD8 T cells from HIVneg donors did not suppress but rather enhanced HIV-replication specifically in macrophages. Finally, when CD8 T cells and HIV-infected macrophages from elite controllers were separated by a transwell membrane, CD8 T cells did not suppress but rather enhanced HIV replication, indicating that HIV suppression was cell-contact dependent while soluble factors may be responsible for enhanced HIV replication. In summary CD8+CD56+ cells have innate antiviral activity in both elite controllers and uninfected donors, while CD8+ T cells have specific antiviral activity in HIV+ donors. In some cases inflammatory CTL may enhance viral replication.
Inflationary expansion and maintenance of an MHC class Ib-restricted response to polyomavirus infection differ in their dependence on CD4 T cell help and CD28 costimulation. (105.45)
Authors: Hofstetter Amelia , Ford Mandy , Hadley Annette , Mlaver David , Pack Christopher , Tompkins S. , Lukacher Aron 
Published: January 2023

Abstract
We recently identified a protective MHC class Ib-restricted CD8 T cell response to infection by mouse polyomavirus (PA Swanson et al. 2008. JEM 205). These CD8 T cells recognize a peptide corresponding to amino acids 139-147 of the VP2 capsid protein presented by the nonpolymorphic Q9 molecule. This Q9:VP2.139-specific CD8 T cell response exhibits inflationary kinetics in MHC class Ia-deficient mice - a gradual expansion in the first three months post-infection with minimal contraction thereafter. We previously demonstrated that Q9:VP2.139-specific CD8 T cells are dependent on antigen for their expansion, but not for their long-term maintenance (PA Swanson et al. 2009. JI 182). Here, we tested the hypothesis that the expansion and maintenance phases of the Q9:VP2.139-specific T cell response are also differentially dependent on CD4 T cell help and CD28 and CD40 ligand costimulation. Either in vivo CD4 cell depletion or CD28/CD40L costimulation blockade inhibited expansion of Q9:VP2.139-specific CD8 T cells. We further found that CD28 blockade alone was sufficient to impair this expansion. In contrast, CD4 cell depletion, but not CD28/CD40L blockade, during the maintenance phase resulted in a decline in frequency of Q9:VP2.139-specific CD8 T cells. These results indicate that the Q9:VP2.139-specific CD8 T cell response depends on CD4 T cell help and CD28 costimulation for its inflationary expansion, but only on CD4 T cell help for its maintenance.
Reverse correlation between CD39+CD25+ Treg and activated CD8+ T cells / NK cells in HIV-1- patients with low CD4 cell counts (105.48)
Authors: Schuler Patrick , Buchanan William , Riddler Sharon , Whiteside Theresa , Bernard Macatangay , Rinaldo Charles 
Published: January 2023

Abstract
The role of regulatory T cells (Treg) in HIV has been studied intensely but remains unclear regarding their effect on cellular immune activation. Frequencies of CD4 and CD8 T cells, CD39+CD25+ Treg, Th17 cells, MDSC, B cells, NK cells and the activation status of T cells (CD38+HLADR+) were determined by flow cytometry in 10 healthy controls and 32 HIV-1+ patients. Immunosuppressive functions of single-cell sorted Treg were determined in the CFSE proliferation assay. Cytokine production (IL1b, 2, 4, 5, 6, 8, 10, INFg, TNFa, GM-CSF), C-reactive protein and soluble CD14 were measured in patients’ plasma by Luminex and ELISA. The absolute number of CD39+CD25+ Treg was significantly decreased in HIV-patients compared to normal controls (p=0.001). However, the frequency of Treg (p=0.04) and HLADR+CD38+CD8+ T cells (p=0.05) was increased only in patients with anti-retroviral therapy (ART). HIV+ patients with ART and low CD4+ cell count had the highest level of immune activation (p=0.04), and in this group we observed a significant negative correlation between CD39+CD25+ Treg and activated T cells (r2=0.5) as well as increased numbers of NK-cells. In ART-treated HIV+ patients with CD4+ T cell recovery, the frequency of Treg, NK cells and CD8+ T cell activation normalized. ART restores the frequency of Treg and activated T cells to normal levels. However, in patients whose CD4+ T cell count did not recover during ART, Treg frequency negatively correlated with T cell immune activation.
The clinical use of cord blood-derived virus-specific cytotoxic T lymphocytes reactive against Cytomegalovirus, Adenovirus, and Epstein-Barr Virus (105.50)
Authors: Hanley Patrick , Martinez Caridad , Leung Kathryn , Cruz Conrad Russell , Savoldo Barbara , Rodgers John , Leen Ann , Dotti Gianpietro , Gee Adrian , Rooney Cliona , Heslop Helen , Krance Robert , Shpall Elizabeth , Bollard Catherine 
Published: January 2023

Abstract
CMV, EBV and Ad-specific CTL(mCTL) have been used successfully to treat these viruses after HSCT. However, the development of virus-protective T cell therapy for patients undergoing CB Transplantation (CBT) requires the priming and extensive expansion of naïve T cells rather than the more limited and simple direct expansion of pre-existing virus-specific memory T cell populations from virus-experienced donors. We have developed a novel protocol utilizing an initial round of stimulation with CB-derived dendritic cells transduced with a recombinant Ad5f35-CMVpp65 vector in the presence of IL12, IL15 and IL7, followed by weekly stimulations with Ad5f35-CMVpp65-transduced EBV-LCL. CB-derived mCTL generated for clinical use from only 20-40 million CB mononuclear cells showed specificity for all 3 viruses and contained a mean of 48% CD8+ and 42% CD4+ cells with various stages of memory T cells. Two patients received mCTL on day 63 post-CBT. One patient remains negative for all 3 viruses. In the other patient, elevated CMV DNA levels were observed in the peripheral blood (PB) 4 weeks post CTL. The CMV cleared within 2 weeks of additonal CTL therapy corresponding to a 31-fold rise in CMV-CTL in the PB. The patient also developed Ad+ diarrhea which resolved without additonal therapy. In summary, we are the first to deliver antigen-specific CTL from CB: infusion of these cells increased virus-specific T cells in the PB dramatically earlier than observed immune reconstitution post CBT.
Viral persistence and fatal CD8 T cell-associated pathology are consequences of NK cell-mediated killing of activated CD4 T cells (105.6)
Authors: Waggoner Stephen , Selin Liisa , Welsh Raymond 
Published: January 2023

Abstract
Natural killer (NK) cells directly control virus replication during some infections and are postulated to indirectly regulate antiviral immunity during other infections through modulation of antiviral T cell responses, but the consequences and mechanisms of this regulation remain largely unexplored. Using the relatively NK cell-resistant lymphocytic choriomeningitis virus (LCMV), we identified a crucial role for NK cells in repression of antiviral T cell responses to a degree that alters the balance between virus clearance and immune pathology. Depletion of NK cells prior to infection of mice with a LCMV clone 13 dose (2 x 105 PFU) normally associated with fatal T cell-mediated immunopathology completely prevented virus-associated morbidity and promoted rapid viral clearance. In contrast, mice depleted of NK cells succumbed to a higher viral dose (2 x 106 PFU) normally associated with non-lethal persistent infection and clonal exhaustion of T cells. During the first three days of infection, NK cells eliminated activated CD4 T cells in a perforin-dependent manner. This early NK cell-mediated decrease in CD4 T cells resulted in lower numbers and diminished cytokine-producing capacity of LCMV-specific CD8 T cells. Thus, NK cells can dramatically alter viral clearance and infection-associated immunopathology by reducing the ability of CD4 T cells to support antiviral CD8 T cell responses in the context of high viral loads and disseminated infection.
Late interleukin-6 promotes T follicular helper cell response and resolution of chronic viral infection (105.8)
Authors: Harker James , Lewis Gavin , Mack Lauren , Zuniga Elina 
Published: January 2023

Abstract
Multiple inhibitory molecules create a profoundly immunuosuppressive environment during chronic viral infections in humans and mice, making generation of effective immunity in this context a challenge. Using murine chronic lymphocytic choriomeningitis virus (LCMV) infection we found that non-hematopoietic cells produced interleukin 6 (IL-6) in a unique biphasic manner, with later IL-6 playing an essential role for viral control. The underlying mechanism involved IL-6 upregulation of the transcription factor BCL6 in virus specific CD4 T cells during chronic (but not acute) infection. This resulted in escalation of T follicular helper cell, germinal center and antibody responses at late stages of chronic infection. Notably, while CD4 T cells showed intact IL6 signaling both early and late after chronic infection only late IL6 stimulation resulted in significant BCL6 up-regulation. Finally ablation of the common IL-6 cytokine family receptor gp130 not only curtailed BCL6 upregulation in CD4 T cells but also reduced their numbers and IL-21 expression in a cell-intrinsic fashion. Our results uncover a novel antiviral strategy that overcomes the immunosuppressive environment to promote CD4 helper functions and safely resolves a persistent infection in vivo. These findings could illuminate new therapies to control viral persistence in humans.
Domain-specific variation in hemagglutinin-specific T-cell responses elicited by licensed seasonal influenza vaccines (106.11)
Authors: Basha Saleem , Hazenfeld Staci , Brady Rebecca , Subbramanian Ramu 
Published: January 2023

Abstract
Persistent antigenic drift in influenza hemagglutinin (HA) results in the emergence of serologically novel influenza viruses that result in seasonal epidemics globally. While the globular domain of the HA antigen is the primary repository of drift mutations, the viral-fusion domain is highly conserved. T cells are being increasingly recognized as a significant component of influenza immunity in humans and may target variant regions of HA that are not effectively targeted by type-specific antibodies. While a trivalent inactivated influenza vaccine (TIV) and a live-attenuated influenza vaccine (LAIV) are now licensed for use in humans, their comparative ability to elicit T cell responses against influenza HA is not well understood: specifically, the relative magnitude of T cell responses elicited by TIV and LAIV and their domain-specificity toward HA regions is unknown. In this study, we systematically compare immune responses elicited by TIV and LAIV in a cohort of healthy adults (18 to 49 years old) against the rapidly evolving H3N2 HA antigen. Data suggests TIV elicits higher geometric mean antibody titers than LAIV; whereas, LAIV elicits superior T cell responses. Importantly, the two vaccines vary significantly in their ability to elicit T cell responses targeting the variant and conserved regions of HA. These results have important implications for the deployment of influenza vaccines in years of antigenic mismatch and shift.
The B-subunit of ricin toxin is involved in eliciting protective antibodies (106.18)
Authors: Yermakova Anastasiya , Mantis Nicholas 
Published: January 2023

Abstract
The ricin toxin B subunit (RTB) is a galactose-specific lectin that promotes attachment and entry of the ricin enzymatic subunit (RTA) into host cells. RTB is an appealing alternative to RTA-based vaccines, because it is non-toxic and inherently antigenic. However, the degree to which RTB elicits protective immunity against ricin remains unresolved. Here we report that parenteral immunization of mice with RTB elicited high ricin-specific serum antibody titers, yet conferred only partial protection against systemic ricin challenge. Analysis of ~2000 RTB-specific B cell hybridomas identified only a handful of neutralizing monoclonal antibodies (mAbs). Two neutralizing mAbs, 24B11 and SylH3, were shown by passive immunization to be sufficient to protect mice against a 5xLD50 dose of ricin. Both 24B11 and SylH3 blocked ricin attachment to terminal galactose residues and prevented toxin binding to primary macrophages, suggesting that they function by steric hindrance and recognize epitopes located on RTB’s galactose binding sub-domains, 1α or 2γ. By contrast, analysis of four non-neutralizing mAbs revealed that they recognized epitopes situated within sub-domains of RTB not involved in galactose recognition (i.e., 1β, 2α). Based on these data, we propose using specific RTB sub-domains as antigens, rather than RTB itself, as a means to more efficiently elicit neutralizing antibodies and protective immunity against ricin.
Passive oral rice-based antibody prophylaxis and therapy against rotavirus infection (106.19)
Authors: Tokuhara Daisuke , Gonzalez Beatriz , Mejima Mio , Takahashi Yuko , Kurokawa Shiho , Hiroiwa Tomoko , Kuroda Masaharu , Oyama Masaaki , Kozuka-Hata Hiroko , Nochi Tomonori , Aladin Farah , Marcotte Harold , Frenken Leon , Iturriza Miren , Kiyono Hiroshi , Hammarstrom Lennart , Yuki Yoshikazu 
Published: January 2023

Abstract
Rotavirus-induced diarrhea is a life-threatening disease in children in developing countries. We have developed a novel system for prophylaxis and therapy against rotavirus using transgenic rice expressing the neutralizing variable domain of llama heavy-chain antibody fragments against rhesus-monkey rotavirus serotype G3P (MucoRice-ARP1). MucoRice-ARP1 was produced at high levels in rice seeds using an overexpression system and RNAi technology to suppress the production of major rice endogenous storage proteins. MucoRice-ARP1 was water-soluble and expressed in protein body II as a rice storage organelle and cytoplasm between protein bodies of in rice. We confirmed the full sequence of 123 amino acids of ARP1 by mass spectrometry. MucoRice-ARP1 neutralized human RV strains (ST-3 G4P[6], 69M G8P[10], F45 G9P[8], P G3P[8] and Va70 G4P[8]) in vitro. When administered orally, MucoRice-ARP1 markedly decreased the prevalence of diarrhea and viral load in a murine pup model. Long-term storage (&gt;1yr) at room temperature of MucoRice-ARP1 did not impair its in vivo neutralizing activity. Oral MucoRice-ARP1 thus offer a novel cost-effective approach to prevent and treat rotavirus-induced diarrhea not only in children but also in adults who would not be expected to respond to the live attenuated vaccine.
Design of T cell epitope rich OmpC peptide and its conjugation with Vi-polysaccharide: a candidate vaccine for typhoid fever (106.26)
Authors: Haque Shabirul , Jailkhani Bansilal , Sengupta Sanjukta , Mukhopadhyay Asok , Bhan Maharaj kishan , Kumar Ramesh 
Published: January 2023

Abstract
Here, we conjugated Vi polysaccharide with outer membrane protein C (OmpC) peptide-39 amino acid residues of S.Typhi and its immunogenicity was evaluated in mice. T cell epitopes in the OmpC were predicted using program T sites. Predominantly two regions with high content of T-cell epitopes, loop # 3a & 7 were chosen and synthesized commercially. Carbodiimide-mediated conjugation of Vi polysaccharide with synthetic OmpC peptide was achieved using ADH as a linker molecule. In various batches; obtained polysaccharide/peptide ratio was between 0.43-0.65. Total and IgG antibodies against Vi polysaccharide and OmpC peptide were measured by ELISA. No Vi antibody was detected in OmpCp and saline control group. Vi polysaccharide alone elicited very low levels of Vi antibody without any booster effect while Vi-OmpCp conjugate evoked 20 fold more efficient immune response than Vi polysaccharide. The Vi-OmpCp conjugate elicited strong booster response which persisted for longer duration. Further, adequate level of IgG antibodies were induced only by the Vi-OmpCp conjugate suggesting that T-helper cells had been induced. Although no immune response was generated against OmpCp. Therefore, selected OmpC short peptide used as carrier with Vi is assumed to be a promising candidate vaccine against typhoid fever.
Antibody-blockade of a Type I interferon receptor decoy cures a viral disease by restoring liver interferon signaling (106.27)
Authors: Xu Renhuan , Sigal Luis 
Published: January 2023

Abstract
Type 1 interferons (T1-IFNs) play a major role in antiviral defense. Orthopoxviruses, including those that produce smallpox and mousepox encode a decoy receptor for T1-IFN, the T1-IFN binding protein (T1-IFNbp), which is essential for virulence. We demonstrate that during mousepox, T1-IFNs protects locally in the liver rather than systemically, and that the T1-IFNbp attaches to uninfected cells surrounding infectious foci in the liver to impair their ability to signal interferon, thus facilitating virus spread. Remarkably, this process can be reverted late in infection by treating with antibodies that block the biological function of the T1-IFNbp. Our findings provide insights on how T1-IFNs function in vivo during viral infection, the first evidence on how an immune evasion gene operates in vivo, and unveil a novel mechanism for antibody-mediated antiviral therapy.
T cell responses in rheumatoid arthritis patients treated with TNF antagonists (107.7)
Authors: Roumanes David , Kobie James , Cavenaugh James , Quataert Sally , Mosmann Tim 
Published: January 2023

Abstract
Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by the overproduction of pro-inflammatory cytokines such as TNFα and IL1. An effective RA treatment is to block the action of TNFα with inhibitors. Due to the central role of TNFα in the inflammatory phase of the immune response, we investigated whether diminishing the TNFα level could lead to an impaired T cell response in RA patients. We first measured a panel of 71 proteins in the serum of healthy donors, early/new RA patients without any treatment and RA patients under anti-TNF therapy. We detected higher levels of several chemokines and cytokines in RA patients. Most levels returned to near-normal values after TNF antagonist therapy, but some chemokines showed no alterations in levels either in RA subjects or after therapy. We then evaluate T cell cytokine secretion by 16-color flow cytometry. A previous in vitro study showed that proliferative responses to recall antigens were reduced in RA patients, but these responses were restored after TNFα antagonist treatment. In contrast, ex vivo analysis of antigen-induced cytokine secretion (after 10 hours) in our studies showed that normal, RA and TNF antagonist-treated patients all showed recall responses against influenza antigens.
Inducible expression of kallikrein in kidney tubular cells protected mice from spontaneous lupus nephritis (107.8)
Authors: Li Quanzhen , Shao Xinli , Yang Ru , Li Yajuan , Xie Shangkui , Mohan Chandra , Igarashi Peter 
Published: January 2023

Abstract
Inducible gene modification using the Cre/loxP system provides a valuable tool for analysis of gene function in specific tissues of live animals. To investigate the therapeutic role of kallikreins (klk) against spontaneous lupus nephritis, we created a transgenic mouse model, KSP-CreERT2/CAG-LacZ(flox)-mKlk1-GFP/Sle1Sle3. This model is based on the expression of a tamoxifen-inducible Cre recombinase under the control of kidney specific promoter (KSP), and its activation will cause the deletion of loxP-flanked LacZ gene and turned on the mKlk1 expression under the control of CAG promoter. In the transgenic mice, the expression of CreERT2 was restricted to KSP+ kidney tubular cells. The transgenic mice were injected with either tamoxifen or vehicle (controls) at 3-mo age and followed up for 6 months for the klk expression and nephritis phenotype. The elevated expression of mKlk1 in the kidney and urine was detected in tamoxifen induced mice but not in controls. At 9-mo age, more than 80% of vehicle injected mice developed severe lupus nephritis as evidenced with increased level of serum BUN (72 ±23mg/dL), proteinuria (21±7mg/24hr) and renal pathology. However, the tamoxifen injected mice showed significantly reduced level of serum BUN(17±8mg/dL), proteinuria (7±3mg/24hr) and mild or no renal pathology change (p&lt;0.05). Tamoxifen induced upregulation of mKlk1 in mouse kidney increased the NO production and suppressed the apoptosis of kidney tubular cells in B6.Sle1.Sle3 mice.
Prostaglandin I2 regulates IL-17 production by invariant natural killer T cells (108.7)
Authors: Simons Bryan , Ferrini Maria , Jaffar Zeina , Roberts Kevan 
Published: January 2023

Abstract
PGI2 is an immunoregulatory prostanoid that is known to limit allergic inflammation. Our previous studies have shown that the PGI2 receptor, IP, also plays an important role in the development of IL-17-producing γδ T cells. Using mice lacking the PGI2 receptor (IPKO), we have investigated whether PGI2 is required for programming invariant natural killer T cells (iNKT) to produce IL-17. The GalCer response of spleen cells from the IPKO mouse was markedly reduced compared to wild type (WT) control animals. Paradoxically, the IL-17 production elicited by iNKT cells isolated from the lungs of IPKO mice stimulated with GalCer was 1.7-5.7 fold elevated over WT control animals. The elevated GalCer response in IPKO lungs was not associated with an increase in CD1d expression or the number of CD4+NK1.1+ or CD4+DX5+ iNKT cells in the lung. The exposure of IPKO animals to 1.5 ppm O3 resulted in a further increase in IL-17 production by lung mononuclear cells (LMC) in response to GalCer. These observations are consistent with iNKT responses being limited by a suppressive mechanism operative in the WT, but not IPKO lung tissue. The regulatory cells were not γδ T cells since the IL-17 produced by LMC in mice lacking the δ TCR chain remained low. Collectively, these results demonstrate that the GalCer response in normal lungs is depressed by a PGI2 dependent mechanism. The role for PGI2 in promoting the regulation of iNKT cells by regulatory cells, including CD4+ nTreg will be discussed.