bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trp53 inactivation in lymphoid-like stroma enhances their survival and immunoregulatory function (P1092)
Authors: Guo Gang , Marrero Luis , Del Valle Luis , Ochoa Augusto , Cui Yan 
Published: January 2023

Abstract
The tumor suppressor p53, a crucial gene in controlling cell cycle and apoptosis, is inactivated via somatic mutations in inflamed tissues, such as synovial fibroblasts of rheumatoid arthritis and cancer infiltrating fibroblasts. Recent studies by our laboratory and others suggest that p53 inactivation in immune cells promotes a pro-inflammatory host microenvironment - elevated serum inflammatory cytokines/chemokines, and enhanced Th17 cells, and augmented differentiation of myeloid cells, including myeloid derived suppressors (MDSCs). Recently, compelling evidence suggests that stroma of the secondary lymphoid organs (SLO) also plays a vital role in immune regulation. We, thus, examined the potential immunomodulatory function of p53null stroma for host immune microenvironment. While the frequency of CD45- stroma in the SP and BM of p53null mice did not differ from that of WT mice, p53null, but not WT, stroma was readily expanded in culture, as well as in the spleen of B16F1tumor bearing p53nullmice. The stromal cells were CD106hiCD54+GP38+Sca-1lo/- fibroblastic reticular cell (FRC)-like that expressed high levels of proinflammatory cytokine/chemokine and immunosuppressive mediators. They enhanced the survival and differentiation of MDSCs and likely regulate the function of other immune cells. Together, our results suggest that p53null stroma is highly immunosuppressive, which modulates host immune-microenvironment via cytokine/chemokine and stroma-immune cell interaction.
Langerhans cell and CD103+ dermal dendritic cell promote Tfh in the steady-state (P1094)
Authors: Igyarto Botond , Jarrett Elizabeth , Zurawski Sandra , Zurawski Gerard , Kaplan Daniel 
Published: January 2023

Abstract
Directing antigen to dendritic cells via antibody/antigen conjugates that target antigen-uptake receptors is a highly efficient vaccination technique and also allows for in vivo examination of the effect of antigen presentation by particular DC subsets. Classic experiments determined that antigen presentation in the absence of DC activation led to deletional tolerance. To study the effects of antigen presentation isolated to LC or CD103+ dDC in the steady-state, we performed a series of experiments in which either 1) transgenic mice that express human Langerin only in LC were immunized with anti-human Langerin/antigen complexes or 2) mice lacking LC were immunized with anti-mouse Langerin/antigen complexes. In both cases the DC remained unactivated and antigen was exclusively found on either LC or CD103+ dDC, respectively. Both DC subsets, were able to promote proliferation of MHC-II tetramer binding endogenous CD4 T cells that peaked at day 7 and slowly declined over time without evidence of deletion. Both subsets induced strong expansion of a population of antigen-specific CXCR5+, PD-1+ CD4 T cells that expressed IFNγ, IL-21 and IL-4 which is most consistent with follicular helper T cells (Tfh). In addition, immunization led to the formation of germinal centers in regional LN and was accompanied with a robust humoral response. Thus, presentation in the steady-state by LC and CD103+ dDC promotes Tfh and humoral responses but not deletional tolerance.
Myeloid-derived suppressor cells ameliorate the pathogenesis of autoimmune arthritis (P1058)
Authors: Crook Kristen , Weeks Michael , Rampersad Rishi , Baldi Robert , Liu Peng 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSCs) are subtypes of monocytes and granulocytes that suppress T cell activity in diseases like cancer and multiple sclerosis. Our previous studies suggested a subset of monocytes may act as MDSCs in autoimmune arthritis. Using the collagen-induced arthritis (CIA) model we identified an increase in the Ly6Chigh subset of monocytes in the periphery of WT mice with CIA compared to naïve mice. This subset was absent from the periphery of CCR2-deficient mice and these mice developed more severe CIA disease. Ly6Chigh monocytes isolated from immunized mice inhibited collagen-activated CD4+T cell proliferation as well as reduced the overall T cell numbers. In the presence of Ly6Chigh monocytes we observed high levels of nitric oxide in the supernatants and an increase in Annexin V positive CD4+T cells. To examine the biological role of these monocytes, we performed a cell-based treatment assay. Compared to control mice, in vivo transfer of Ly6Chigh monocytes to collagen-immunized mice resulted in delayed onset of disease, reduced joint swelling, decreased IL-6, IL-1β, and IFNγ expression in the joints and decreased IL-6 and IL-17 levels in the serum. In summary, Ly6Chigh monocytes function as MDSCs to inhibit CD4+T cell proliferation and survival. In vivo transfer of Ly6Chigh monocytes ameliorated autoimmune arthritis in the CIA model suggesting these cells could potentially be used in cell-based therapies for treatment of rheumatoid arthritis.
Cytokine profiles in patients with Staphylococcus aureus skin infections (P3136)
Authors: Chen Luqiu , Bartman Caroline , Chong Anita , Daum Robert , Alegre Maria-Luisa 
Published: January 2023

Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) causes skin infections in epidemic proportions among otherwise healthy individuals. Previous evidence shows that Th17 cells may be crucial to prevent localized S. aureus infections, as they occur in patients deficient in STAT3 or mice lacking IL-17A and F. In this study, we hypothesized that patients presenting to the emergency room (ER) with skin infections but no known genetic deficiency may have a reduction in Th17 differentiation, either globally or specifically to S. aureus antigens because of inhibitory factors produced by MRSA strains. Sera from 72 patients and 143 controls were collected and cytokines were measured by MultiPlex beads assay. It showed elevated cytokines in patients with skin abscesses on day 0. PBMCs from the same groups were stimulated with MRSA lysates, or anti-CD3, and supernatants were collected at 24h for detection of cytokines by ELISA. The production of IFNγ and IL-17 in response to anti-CD3 was similar in patients and controls, but MRSA stimulation triggered greater secretion of IL-6 and IFNγ in select groups of patients than in controls. These data suggest that our skin infected patients do not have a global defect in Th17 differentiation but may have a specific increase in IFNγ production in response to S. aureus antigens. Future experiments in mice will investigate whether this response may be detrimental to prevent S. aureus infections.
Environmental perturbation and behavioral fatigue in healthy and virus-infected mice (P3112)
Authors: Trammell Rita , Toth Linda 
Published: January 2023

Abstract
Introduction: High antibody titers to Epstein-Barr virus occur in some patients with chronic fatigue syndrome. We hypothesized that inflammatory immune responses to reactivation of latent virus may trigger or exacerbate fatigue particularly under stressful conditions. To test this hypothesis, we exposed mice latently infected with murine gammaherpesvirus (MuGHV) and uninfected mice to environmental stressors or basal non-stressful conditions and measured the impact of these challenges on indices of behavioral fatigue and markers of inflammation. Results: Exposure of mice to environmental stressors during the normal somnolent phase was associated with behavioral signs consistent with fatigue during the subsequent active phase. These signs of behavioral fatigue develop despite an intervening rest period and were only marginally affected by infection status. Under basal non-stressful conditions, there was increased inflammation in lung of infected versus uninfected mice with no significant differences observed in serum. In contrast, exposure to stress for 6 h was associated with inflammatory responses in both serum and lung regardless of infection status. Conclusion: Our study has shown that exposure of mice to environmental stressors is associated with signs of behavioral fatigue and systemic inflammation in a manner that is largely independent of latent viral infection with MuGHV.
Chemically induced intestinal inflammation was suppressed in progeny of Trichinella spiralis infected mice. (P3118)
Authors: Cho Min Kyoung , Park Mi Kyung , Kang Shin Ae , Yu Hak Sun 
Published: January 2023

Abstract
Recently, there are many reports that worm infections during pregnancy have important immunological effects on the progeny. In previous study, we confirmed that the Trichinella spiralis infection could inhibit chemically induced intestinal inflammation. In this study, we investigated if the immune regulation in T. spiralis infected mice could be persisted to their progeny. We obtained the progeny from T. spiralis infected female mice or no infected mice and induced intestinal inflammation by dextran sulfate sodium (DSS). As the results, loss of body weight and increased disease activity index (DAI) value were caused by DSS, but these responses were significantly suppressed in the progeny of T. spiralis infected mice than those of the progeny of uninfected mice. Moreover, IL-1β, TNF-α, IL-6 and IL-17 cytokines level was decreased in the progeny of T. spiralis infected mice. Additionally, this down-regulation of intestinal inflammation was observed in the breast milk-fed progeny from T. spiralis infected mice, but is not generated from infected mice. In the progeny fed breast milk of T. spiralis infected mice, DAI value, degree of weight loss and the level of inflammatory cytokines were significantly lower than those in the progeny fed breast milk of no infected mice. In order to find T. spiralis molecules that could be transferred to the progeny, we performed western blot. In the result, we confirmed three T. spiralis molecules in the breast milk of T. spiralis infected mice.
Bystander CD8 T cells produce granzyme B and promote exacerbated disease during Leishmania major infection (P3079)
Authors: Crosby Erika , Wherry E. , Scott Phillip 
Published: January 2023

Abstract
CD8 T cells are recruited to inflamed tissue independent of their antigen specificity, but whether CD8 T cells with irrelevant specificities contribute to the immune response is unclear. We found that Lymphocytic choriomeningitis virus (LCMV)-specific CD8 T cells from a previous LCMV infection were recruited in large numbers to leishmanial lesions in mice infected with L. major. Importantly, LCMV immune mice developed larger leishmanial lesions than naïve mice, associated with increased CD8 T cell, neutrophil and monocyte infiltration into the lesions. The recruited CD8 T cells produced granzyme B and increased levels of circulating granzyme B were detected in the serum of LCMV immune mice that had been challenged with L. major, suggesting that granzyme B may be promoting the increased inflammation. This prompted us to determine what cytokines might stimulate the production of granzyme B from previously activated CD8 T cells in the absence of T cell receptor signaling. We found that IL-15 induced granzyme B, but not IFN-γ, expression. In contrast, IL-12 + IL-18 induced IFN-γ but little granzyme B expression. Thus, our findings demonstrate that bystander CD8 T cells can influence the outcome of subsequent infections, and that the cytokine milieu may dictate how the bystander memory CD8 T cells respond within inflamed sites.
Lung infiltrates containing myeloid-derived suppressor cells impair protective immunity in pneumonic tularemia caused by Francisella tularemia (P3082)
Authors: Periasamy Sivakumar , Sellati Timothy , Harton Jonathan 
Published: January 2023

Abstract
Inhalation of low (~10) numbers of Francisella tularensis, a biothreat category ‘A’ agent, causes acute pneumonia and death; two key features of pneumonic tularemia emphasizing deficiency in the host response to pathogen. We previously reported that early establishment of an immunosuppressive milieu in the lungs favored unfettered and exponential growth of F. tularensis in mice, suggesting a role for immunosuppressive cells in the pathogenesis of tularemia. A comprehensive multicolor flow cytometer analysis for immune cells in the lungs and spleen was performed to address this issue. F. tularensis-infected mice had a high frequency of infiltrating myeloid (CD11b+) cells, but no change in the frequencies of B220+, CD4+, or CD8+ lymphoid cells in lungs and spleen. A majority of the infiltrating myeloid cells were CD11b+CD11c-Ly6G+Ly6C+, a phenotype consistent with immature or myeloid-derived suppressor cells (MDSC). The frequencies of neutrophils (Gr-1+F4/80-) and macrophages (Gr-1-F4/80+) were also increased. Consistent with myeloid cell recruitment, levels of mouse KC, MCP-1 and IL-17A were increased in the lungs. Despite a rapid accumulation of myeloid cells in the lungs, these cells fail to control bacterial replication. Our results suggest that a significant portion of the CD11b+CD11c-Ly6G+Ly6C+ infiltrating cells are likely MDSC, which impair protective immune responses and cause necrotizing inflammation in the lungs and death of F. tularensis-infected mice.
Liver induced immunosuppression by Salmonella-specific CD4 T cells during persistent infection (P3097)
Authors: Kurtz Jonathan , McLachlan James 
Published: January 2023

Abstract
What role microenvironments play in dictating immune outcomes during infection is largely unknown. Our lab uniquely combines a murine model of persistent S. typhimurium infection with recombineered Salmonella strains and MHC-II tetramers to visualize endogenous Salmonella-specific CD4 T cell responses during infection in various organs. We hypothesize that an immunological stalemate between bacterial persistence and the host immune response is determined by anatomical location, which dictates T cell function and infection outcome. We show Salmonella-specific CD4 T cells adoptively transferred from lymphoid organs protect mice from subsequent challenge, while CD4 T cells transferred from infected livers increase susceptibility. Furthermore, lymphoid Salmonella-specific Th1-cells produce higher levels of interferon-γ, while FoxP3- liver CD4 T cells produce larger amounts of interleukin-10, with a decreased proliferative capacity. Additionally, we show lymphoid Th1 cells are potent activators of iNOS and reduce macrophage bacterial loads, while liver-derived Tr1-like cells fail to control bacterial replication, through attenuated iNOS activation. Whether these immunosuppressive Tr1-like cells are induced in the liver, or phenotypically switch upon entering the organ, remains under investigation. These results demonstrate that during persistent Salmonella infection different immunological responses occur at different anatomical sites, which may dictate the outcome of infection.
CD4+CD25+ T regulatory cells dampen inflammatory responses in murine mycoplasma pneumonia and are associated with promotion of IL-17 AND IFN-γ production, but not IL-10 or TGF-β. (P3055)
Authors: Simecka Jerry , Odeh Adam 
Published: January 2023

Abstract
Mycoplasmas cause respiratory diseases characterized by persistent infection and chronic airway inflammation. Mycoplasma lung disease is immunopathologic, with Th cells determining disease severity and resistance to infection. Th2 cell responses promote immunopathology; Th1 cells confer resistance to infection. However, little is known about the role of Treg cells in mycoplasma respiratory diseases. We hypothesized Treg cells control the severity of the inflammatory lesions and may also promote persistence of infection, as found in other diseases. To examine this, mice, given anti-CD25 antibody to deplete Treg cells, had increased disease severity due to Mycoplasma pulmonis infection. There was however no affect on mycoplasma numbers recovered from the lungs. Treg cells promote the secretion of IFN-γ and IL-17 mycoplasma-specific CD4+ T cell responses in vitro. We were unable to detect significant changes in IL-10 and TGF-β production. In addition, Treg cell depletion increased Th2 (IL-13) responses. Populations of Treg cells from lymph nodes had increased expression of IFN-γ or IL-17 after infection. Thus, Treg cells play an important role in controlling damaging immune responses in mycoplasma respiratory infection but do not influence the level of mycoplasma infection. It appears that Treg cells dampen mycoplama inflammatory disease through a novel mechanism mediated production of IFN-γ and IL-17.
The Eph/Ephrin molecules are modulated in organs of parasitized red blood cells sequestration and may contribute to disease pathogenesis in rodent malaria. (P3059)
Authors: Mimche Patrice , Brady Lauren , Cox Daniel , Lamb Tracey 
Published: January 2023

Abstract
Eph receptors and their Ephrin ligands are the largest family of receptor tyrosine kinases. Beyond their role in cell trafficking/adhesion and cancer, nothing is known about their activation during malaria infection. We explored the regulation of Eph/Ephrin in malaria using the rodent malaria model P. berghei ANKA, a parasite that causes experimental cerebral malaria in C57BL/6 mice. Infection with P. berghei ANKA leads to modulation of transcription for some members of the Eph/Ephrin in C57BL/6 mouse brain and spleen. This may be driven by inflammatory cytokines upregulated in these organs in response to sequestration of iRBCs because TNFR2-/- mice which are known to be resistant from death by ECM did not display any upregulation of Eph/Ephrin. To further examine their modulation, subsets of antigen presenting cells and T cells were FACS sorted from splenocytes at different time points post infection. Transcription was found to be modulated between days 2 and 3, particularly for EphB2 on CD11b+ macrophage/neutrophil subset. To support the modulation of transcription in the brain during ECM, mouse primary brain microvascular endothelial cells were isolated from naïve mice and stimulated with inflammatory cytokines and lysates of iRBCs. We observed an increase in the transcription of EphB4 and EphB6 in response to inflammatory cytokine signaling and an increase in the protein expression of EphB4 in response to iRBC lysates. The implications of these results will be discussed.
Acute inflammatory asthma protects influenza infected mice from bacterial superinfection (P3065)
Authors: Samarasinghe Amali , LeMessurier Kim , Iverson Amy , Woolard Stacie , McCullers Jonathan 
Published: January 2023

Abstract
The Centers of Disease Control identified asthmatics to suffer more severe morbidity from influenza during the 2009 pandemic. However, our data indicate that pre-existing allergic inflammation during viral infection is protective against influenza associated disease in mice. Since bacterial super-infections during influenza increase morbidity and mortality, we hypothesized that acute inflammatory asthma promotes bacterial colonization of the lungs after influenza infection thereby leading to a more severe outcome. We created a triple variant model system by infecting Aspergillus fumigatus sensitized and challenged mice with 1000 TCID50/ml of A/CA/4/2009 virus a week after the last fungal challenge. Mice were co-infected with 600 cfu of Streptococcus pneumoniae strain A66.1 a week later and monitored for six days. Mice with allergic asthma lost less weight after co-infection, had less airway resistance after methacholine challenge, and had at least a 50% reduction in mortality compared to non-asthmatic controls. Fewer inflammatory cells were recruited into the airways of allergic mice after co-infection. Allergic asthma delayed S. pneumoniae colonization in the airways and lungs but not blood compared to co-infection alone. Mice in the asthma and co-infection model had less normal flora outgrowth in the airways, lungs, and blood compared to those in the co-infection model. Allergic asthma protects against, or delays, bacterial super-infection after influenza challenge.
Contribution of differentially expressed micro-RNA to functional differences in human blood monocyte subpopulations (P1194)
Authors: Dang Minh , Wong Wing Cheong , Ong Siew Min , Chen Jinmiao , Poidinger Michael , Zolezzi Francesca , Wong Siew Cheng 
Published: January 2023

Abstract
Human blood monocytes can be broadly divided into two subpopulations, CD14+CD16- (CD16-) and CD14+/loCD16+ (CD16+). Although numerous phenotypic and functional differences between the two subsets have already been described, much remains to be learned about the roles contributed by each subset during homeostasis or disease conditions. In this study, we characterize these two monocyte subsets using microRNAs (miRNAs) and messenger RNA (mRNA) array approach. We identified 66 miRNAs to be differentially expressed (DE) between CD16+ and CD16- monocytes. By integrating mRNA expression data with miRNA expression data via negative correlation, we were able to demonstrate that several of these DE miRNAs regulate mRNAs that play important roles in inflammatory response, cell death, cellular development, cellular movement and cell-to-cell signaling and interaction. We validated experimentally the association of miR-432 (expressed higher in CD16+ monocytes) with apoptosis and this might explain why CD16+ monocytes are more susceptible to spontaneous apoptosis seen in our previous study. The association of miR-19a with cell motility was also validated in our experiments and this might explain why CD16+ monocytes (with higher expression of miR-19a) move slower in comparison with CD16- monocytes. Together, our data showed that differentially expressed miRNA contribute to the functional differences in human blood monocyte subpopulations.
TRAF3 restrains regulatory T cell development by modulating IL-2 signaling (P1219)
Authors: Yi Zuoan , Lin Waiwai , Stunz Laura , Bishop Gail 
Published: January 2023

Abstract
The signaling protein TNF receptor associated factor 3 (TRAF3) has multiple diverse effects on signaling transduction. We recently produced a new strain of T cell specific TRAF3 deficient mice (CD4CreTRAF3flox/flox (T-T3-/-)), and found that the frequency and number of Foxp3+ regulatory T cells (Treg) are increased 2-3 times compared with litter mate control mice (LMC), though total CD4+ and CD8+ T cell numbers do not change. These Treg are Helios+ and the increase is cell intrinsic. Interestingly, thymic Treg emerge as early as day 1 after birth in T-T3-/- mice, compared to day 3 after birth in LMC. Notably, the percentage of Treg precursor cells is unchanged. However, following IL-2 stimulation, TRAF3-deficient Treg precursor cells convert into Foxp3+ Treg more efficiently than those of LMC, though expression levels of IL-2 receptor components are comparable. We further found that phosphorylation of STAT5 is remarkably enhanced in TRAF3-/- Treg precursors in response to IL-2 stimulation. We also noticed that T-T3-/- conventional CD4 T cells exhibit robustly enhanced p-STAT5, but not p-ERK and p-AKT, when stimulated with IL-2. Additionally, TRAF3 deficiency affects the plasma membrane localization of T Cell Protein Tyrosine Phosphatase (TCPTP), an enzyme that plays a negative role in IL-2 signaling. Taken together, our data show for the first time that TRAF3 is an important regulator of IL-2 signaling and affects Treg development.