bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pim kinases significantly impact humoral immune responses (IRM12P.648)
Authors: Willems Kristen , Schmidt Madelyn , Woodland Robert 
Published: January 2023

Abstract
The Provirus Integration site for Moloney murine leukemia virus (Pim) family of oncogenic serine/threonine kinases regulates a variety of metabolic functions in hematopoietic cells and lymphocytes. We examined the importance of Pim kinases in B cell activation following antigen stimulation. Humoral immune responses were significantly impaired in Pim 1 and 2 deficient mice (Pim 1-/-2-/-) T cell dependent responses were compromised while T cell independent type 1 and 2 antigen responses were virtually absent. Humoral deficiencies were owing to reduced production of antibody secreting cells due to the diminished induction of BLIMP-1 expression. The central role of Pim in these responses is consistent with our observation that Pims are induced downstream of multiple B cell activation receptors including CD40, BCR, and TLR4. We suggest that Pim 1 and 2 dependent signaling pathways are involved in B cell activation and their loss requires increased signaling through other pathways to reach an activation threshold. This hypothesis is further supported by the initial higher affinity of BCRs on Pim deficient B cells activated in a TD response and their inability to proliferate or undergo isotype switching in culture at the same rate as WT B cells when activator concentrations are decreased. Taken together, these data demonstrate a critical role for Pim kinases in affinity maturation, isotype switching, proliferation and the production of antibody secreting cells by B lymphocytes. .
IL-2 production by activated naïve and effector CD8 T cells forecasts memory formation. (LYM5P.700)
Authors: Kahan Shannon , Bakshi Rakesh , Luther Rita , Harrington Laurie , Weaver Casey , Zajac Allan 
Published: January 2023

Abstract
The clearance and control of many intracellular pathogens and tumors rely on the development of efficacious CD8 T cell responses. These responses are functionally diverse, however, whether and how this heterogeneity forecasts effector formation, memory potential, and protective capacity has not yet been definitively determined. To address this, we utilized IL-2 and IFN-γ double cytokine reporter mice to separate viable IL-2 and IFN-γ producing CD8 T cell subsets, and performed a series of adoptive transfer experiments to track their memory potential and fate. We discovered that within hours of activation, naïve CD8 T cells undergo a burst of cytokine synthesis and distinct populations develop that produce only IL-2, only IFN-γ, co-produce IL-2 and IFN-γ, or do not produce either cytokine. This diversity is consequential as newly activated naïve CD8 T cells that fail to produce IL-2 preferentially attain effector features. Conversely, autocrine IL-2 production by recently activated naïve CD8 T cells is associated with the formation of memory traits. Similarly, the ability of CD8 T cells to produce IL-2 during the effector phase also signified memory potential and the ability to mount vigorous secondary proliferative responses. Together these data demonstrate that functional heterogeneity influences the differentiation of CD8 T cell responses and that effector and memory formation can be predicted by the pattern of autocrine IL-2 production.
Lymphopenia-induced CD4 T cell proliferation leads to bystander activation of CD8 T cells with increased gut-homing specificity (LYM6P.722)
Authors: Kim Juhee , Surh Charles 
Published: January 2023

Abstract
In the presence of high levels of certain cytokines, such as IL-2 and/or IL-15, and self-peptide-TCR interaction, CD8 T cells undergo strong proliferation, referred to as “bystander proliferation”. Up to now, bystander activated CD8 T cells have not been investigated on a role in normal condition. In order to define a role of bystander activated CD8 T cells, we co-transferred OT-I T cells with naïve polyclonal CD4 T cells into conventional immunodeficient Rag-/- mice to make CD4 T cells be activated in response to commensal microbiota and secrete large amount of IL-2. The bystander activated OT-I T cells which were driven by IL-2 from activated CD4 T cells underwent massive proliferation, acquired effector functions, up-regulated a4b7 and migrated into mostly gut. Moreover, we induced OT-I T cells to undergo bystander proliferation in normal conventional B6 hosts by co-injection of smarta CD4 T cells, a strong inducer of IL-2, after LCMV injection and by depletion of host T cells to increase consumption of IL-2 for donor OT-I T cells. Interestingly, bystander activated OT-I T cells driven by IL-2 from activated smarta CD4 T cells in normal conventional B6 hosts also up-regulated a4b7 and migrated into gut. Based on the finding, we will further investigate on the role of bystander activated CD8 T cells to protect against mucosal infection, such as Listeria monocytogenes-OVA (LM-OVA) and the factor for up-regulating a4b7 on bystander activated CD8 T cells.
Long-lived IgM plasma cells confer host protection against viral challenge (LYM6P.717)
Authors: Bohannon Caitlin , Powers Ryan , Satyabhama Lakshmipriyadarshini , Cui Ang , Tipton Christopher , Michaeli Miri , Mehr Ramit , Mittler Robert , Kleinstein Steven , Sanz Ignacio , Jacob Joshy 
Published: January 2023

Abstract
Long-lived plasma cells are critical to immune memory, as they continuously secrete antigen-specific antibodies for up to a lifetime. Antigen-stimulated B cells, with T cell help, undergo affinity maturation within germinal centers and home to the bone marrow microenvironment where they persist as long-lived IgG plasma cells. Here we show that antigen-specific IgM plasma cells can also persist in the spleen for a lifetime. These IgM plasma cells can develop independent of the germinal center. Interestingly, despite being germinal center-independent, these cells exhibited somatic mutations in their expressed IgV heavy chain loci. Finally, we present data that antibodies from these IgM plasma cells can confer protective immunity to the host.
Low surrogate light chain in pro-B cells from old mice suppresses apoptosis and alters the idiotypes and proportions of phosphorylcholine reactive B cells (LYM6P.718)
Authors: Riley Richard , McAvoy Kelly , Ratliff Michelle , Alter Sarah , Frasca Daniela , Khan Wasif , Blomberg Bonnie 
Published: January 2023

Abstract
The generation of new B cells is substantially decreased in old mice (&gt;2 years). Early B cell precursors (pro-B cells) are reduced in old mice and exhibit a reduction in the surrogate light chain (SLC) protein λ5. We hypothesize that this alters the expression and function of the pre-B cell receptor and influences the “read-out” of antibody specificities in the B cell repertoire. In old mice, the remaining pro-B cells, low in SLC, are resistant to apoptotic stimuli (TNFα), in contrast to young adult pro-B cells. Apoptotic sensitivity reflects levels of the SLC, since young pro-B cells partially or completely deficient in λ5 are also resistant to apoptosis. Age-associated B cells (ABC) represent a B cell subset which expands in old mice; ABC are pro-inflammatory and secrete TNFα. Adoptive transfer of ABC into young RAG-2 KO recipients results in partial loss of pro-B cells and, in particular, loss of pro-B cells with higher levels of SLC λ5. Anti-phosphorylcholine (PC) reactive B cells, especially those of the T15 idiotype, are important in defense against pneumococci. In old age, the proportion of PC reactive B cells, particularly with less protective T15 negative idiotypes, increases. Low SLC promotes both increased PC reactivity and T15 negative idiotypes. These studies suggest that ABC promote an “SLClow” B cell pathway that alters antibody specificities in old age.
TNFα-induced epigenetic modifications support a DC1 program in dendritic cells during protective immunity to cryptococcal infection (MPF4P.732)
Authors: Eastman Alison , Potchen Nicole , Carolan Jacob , Malachowski Antoni , Kryczek Ilona , Kunkel Steven , Osterholzer John , Olszewski Michal 
Published: January 2023

Abstract
TNFα is required for protective Th1 immunity to Cryptococcus neoformans (Cneo) and these effects are linked to the stable, early classical activation of dendritic cells (DC1), preventing alternative (DC2) activation. We hypothesized that TNFα stabilizes DC1 DC by inducing epigenetic modification of key DC1 genes. We modeled TNFα-stabilized DC (TSDC) in vitro by treating DC with DC1-skewing IFNγ +/- TNFα followed by a switch to DC2-skewing IL-4, and we assessed transcriptional and epigenetic signatures. Epigenetic studies focused on histone 3 methylation at lysines 4, 9 and 27 (H3K4, 9 or 27, respectively). H3K4 methylation is associated with activation of proximal genes, but H3K9 and 27 methylations are associated with repression. TSDC showed resistance to induction of DC2 genes and increased transcript levels of the key histone methyltransferases G9a (H3K9), EZH2 (H3K27) and MLL1 (H3K4). Further, we performed ChIP on TSDC and found that IL12b and IFNγ promoters are associated with the activating H3K4 methylation while non-stabilized DC1 and DC2 were not. We next assessed EZH2, G9a, and MLL1 transcript levels and the global methylation state of H3K4 in Cneo-infected lungs and found that both mRNA transcript levels and H3K4 methylation increased significantly in control but not TNFα-depleted mice. We conclude that histone modifications in DC are significantly altered by TNFα, and that this correlates with increased DC1 stability during protective responses to Cneo infection.
Large-scale sequencing of antibody responses to Borrelia burgdorferi infection (MPF5P.743)
Authors: Blum Lisa , Lahey Lauren , Kongpachith Sarah , Ju Chia-Hsin , Aucott John , Soloski Mark , Robinson William 
Published: January 2023

Abstract
Patients with Lyme disease present with protean manifestations and kinetics of disease, and these differences cannot be solely attributed to pathogen load or strain. Better understanding of antibody-mediated immunity in the human host is crucial for developing improved diagnostics and could provide insights into immune targeting of B. burgdorferi antigens associated with successful clearance of infection. We have developed an “antibody repertoire capture” (ARC) strategy that utilizes DNA barcodes to enable large-scale sequence analysis of the paired heavy-chain (HC) and light-chain (LC) immunoglobulin (Ig) genes expressed by individual Ig-expressing cells. This method allows us to generate evolutionary trees of the paired (HC+LC) repertoires and thus identify and recombinantly express the affinity-matured antibodies that are likely to drive immune protection and pathogenicity. We have applied ARC to peripheral blood plasmablasts from patients with early (weeks-long) and late (months-long) untreated B. burgdorferi infections. The size and number of clonally expanded Ig families was significantly greater in infections that went untreated for many months. Recombinant mAbs derived from these sequences bound to both host- and pathogen-associated antigens. These human plasmablast-derived mAbs provide us with a powerful tool to interrogate the functions of host antibodies in vitro and in animal models of infection, and may prove to have diagnostic or therapeutic potential.
mTOR mediates IL-23 induction of neutrophil IL-17 and IL-22 production (MUC5P.745)
Authors: Chen Feidi 
Published: January 2023

Abstract
It has been shown recently that neutrophils are able to produce IL-22 and IL-17, which differentially regulate the pathogenesis of inflammatory bowel disease. However, it is still largely unknown how the neutrophil production of IL-22 and IL-17 is regulated, and what the receptors are required. We demonstrated that, in a microbiota antigen specific T-cell mediated colitis model, neutrophils accumulated in the intestines prior to intestinal inflammation. Depletion of neutrophils resulted in a significant increase of colitis development, indicating a protective role of neutrophils in colitis. We found that neutrophils expressed both rorc and ahr. IL-23 promoted neutrophil expression of rorc and ahr, and stimulated production of IL-17 and IL-22. RORgt and AHR differentially regulated IL-23 induction of neutrophil IL-17 and IL-22, in that blockade of RORgt inhibited both IL-17 and IL-22 while AHR inhibitor only inhibited IL-22 but not IL-17 production. IL-23 induced mTOR activation in neutrophils. Blockade of mTOR pathway decreased expression of rorc and ahr, and inhibited IL-23-induced IL-17 and IL-22 production. Collectively, our data indicates that neutrophils negatively regulate microbiota antigen specific T cell induction of colitis, and IL-23 induces neutrophil production of IL-22 and IL-17 through induction of rorc and ahr, which is mediated by mTOR.
The NLRP1 inflammasome attenuates colitis and colitis-associated tumorigenesis (MUC5P.750)
Authors: Allen Irving , Williams Tere , Leeth Rachel , Rothschild Daniel , Coutermarsh-Ott Sheryl , McDaniel Dylan , Simmons Alysha , Heid Bettina , Cecere Thomas 
Published: January 2023

Abstract
NLR proteins are a diverse family of pattern recognition receptors that modulate immune system homeostasis in the gastrointestinal system. Recent studies have identified a sub-group of inflammasome forming NLRs that modulate the mucosal immune response during inflammatory bowel disease (IBD) and colitis associated tumorigenesis. To better elucidate the contribution of NLR family members in IBD and cancer, we conducted a retrospective analysis of gene expression metadata from human patients. These data revealed that NLRP1, an inflammasome forming NLR, was significantly dysregulated in IBD and colon cancer. To better characterize the function of NLRP1 in disease pathogenesis, we utilized Nlrp1b-/- mice in experimental colitis and colitis associated cancer models. Nlrp1b-/- mice demonstrated significant increases in inflammation and tumorigenesis compared to wild type mice. The increased inflammation and tumor burden was correlated with attenuated levels of IL-1β and IL-18. Further mechanistic studies revealed the increased disease pathogenesis in the Nlrp1b-/- mice was associated with non-hematopoietic derived cells and suggests that NLRP1 functions in the colon epithelial cells to attenuate tumorigenesis. Together, these data identify NLRP1 as an essential mediator of the host immune response during IBD and cancer. These findings are consistent with a model whereby multiple NLR inflammasomes attenuate disease pathobiology through modulating IL-1β and IL-18 levels in the colon.
Treatment with a selective histone deacetylase 6 inhibitor decreases lupus nephritis in NZB/W mice (THER5P.910)
Authors: Vieson Miranda , Barrett Sarah , Gojmerac Alex , Reilly Christopher 
Published: January 2023

Abstract
To date, there are 17 histone deacetylase (HDAC) enzymes, divided into 4 classes, which alter protein function by removing acetyl groups from lysine residues. Prior studies report that non-selective HDAC inhibitors decrease disease in various lupus mouse models. Selective HDAC-6 inhibition acts on cytosolic proteins to decrease B cell proliferation and differentiation by inhibiting α-tubulin function. Since B cells play a critical role in the initiation and propagation of systemic lupus erythematosus, we hypothesized that a selective HDAC-6 inhibitor (HDAC6i) will alleviate disease in a mouse model. Intraperitoneal injections of HDAC6i (0.3 mg/kg, 1 mg/kg, or 3 mg/kg), vehicle control, or dexamethasone were administered to 21-week-old, female NZB/W mice, 5 days a week, for 13 weeks. Disease was evaluated by body weight, proteinuria, serum levels of anti-dsDNA antibody, cytokines and immunoglobulins, and post mortem evaluation of nephritis and B cell populations in the bone marrow and spleen. Treatment with HDAC6i decreased glomerular scores, spleen weights, and urine protein scores when compared to vehicle-treated mice. No differences in B cell development and differentiation in the bone marrow, and B cell activation in the spleen were noted. We conclude that HDAC-6 inhibitors are effective at decreasing lupus nephritis and disease in NZB/W mice, however further studies are warranted to investigate the underlying mechanism, particularly in regards to B cell pathophysiology.
Gut bacteria modulation of antigen presenting cells in a mouse model of autoimmune diabetes. (THER5P.915)
Authors: Sidi Mohamed Zaynab , Larkin Joseph 
Published: January 2023

Abstract
T1D is an autoimmune disease whereby the beta cells of the pancreas are destroyed, resulting in the inability to self-regulate blood glucose. While genetics play a role, the contribution of environmental factors such as gut bacteria have also been implicated. Notably, it was shown that the oral administration of L. johnsonii N6.2 (LjN6.2) conveyed diabetes resistance to diabetes prone rodents while a second strain, Lactobacillus reuteri TD1, had no effect. However, the exact mechanisms of microbiota action on diabetes prevention remain poorly understood. As it has been shown that defective antigen presentation by dendritic cells (DC) contributes to T1D progression, we tested the hypothesis that gut flora can serve to modulate DC maturation. We observed that the administration of LjN6.2 to NOD leukocytes in vitro mediated increases in CD11c+MHCII+ DC. Moreover, LjN6.2 facilitated enhanced myeloid dendritic cell maturation denoted by the increase in number of CD8alo DEC205lo that were comparable to levels present in NOR mice. In addition, LjN6.2 also increased IL6 production. This study highlights the role of gut bacteria in autoimmunity as a critical component for T1D therapeutic strategies and might be used to extrapolate treatment approaches in humans in the future.
Sex-dependent response to treatment for arthritis in humanized mice (THER5P.903)
Authors: Taneja Veena 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) occurs twice more often in women than men. B cell depletion has been shown to be efficacious in treating RA though it is unknown if efficacy is dependent on the sex of the patient. Our previous studies suggested that antigen presentation via B cells results in a sex-specific immune response and cytokines in humanized mice. Now we show that the efficacy of B cell depletion in arthritic DQ8 mice is sex-dependent. Arthritic female DQ8 mice treated with anti-CD20 antibody in therapeutic protocols show milder disease severity associated with decreased antibodies to citrullinated proteins along with increased numbers of T regulatory as compared to male DQ8 mice. The milder disease severity in CD20-depleted females was associated with reduced levels of IL-23 and CCL5 with increased IL-13 as compared to males. Treated male mice showed higher numbers of subsets of dendritic cells, known producers of pro-inflammatory cytokines, as compared to females. A window where males can benefit from B cell depletion needs to be defined. Our observations suggest that in therapeutic strategies that target B cells during established disease may benefit females while DCs might be relatively more important for men than women.
TREM1 intervention does not affect renal pathology upon ischemia/reperfusion injury (TRAN1P.929)
Authors: Tammaro Alessandra , Emal Diba , stroo Ingrid , Teske Gwendolin , Butter Loes , Claessen Nike , florquin sandrine , Leemans Jacklien , Dessing Mark 
Published: January 2023

Abstract
Rationale:Following transplantation, renal ischemia is a major cause of Acute Kidney injury(AKI). TREM1(Triggering receptor expressed on myeloid cells 1) is an innate immune receptor expressed on neutrophils and monocytes/macrophages, the most common cells infiltrating the kidney upon IR. TREM1 enhances Toll-like receptor (TLR)-induced inflammatory response in several models of infection and sterile inflammation.TREM1 inhibition reduced disease severity in mesenteric ischemia-reperfusion induced injury (IRI).We hypothesized that TREM1 intervention will also reduce renal IRI. Methods:Mice were subjected to renal IRI induced by occlusion of the renal artery for 25’ and reperfused for 24h. Mice were treated i.p. with different doses of LP17, LR12, TREM1 fusion protein and control peptides.Renal TREM1 protein expression and plasma sTREM1 were measured. TREM1 expression on circulating granulocyte and monocyte, renal function (creatinine, urea), damage (PASD) and inflammation (KC and LY6G-positive cell infiltration) were evaluated. Results:IRI was associated with increased renal and circulating TREM1 protein levels. TREM1 levels were similar on circulating granulocyte but decrease on monocyte upon IR. TREM1 intervention with LP17, LR12 and TREM1 fusion protein did not reduce renal dysfunction, injury or inflammation following IRI. Conclusion: The modulation of the TREM-1 pathway by means of synthetic peptides and fusion protein does not represent a useful tool to prevent renal IRI.
The microbiota accelerates skin graft rejection through enhanced T cell priming (TRAN1P.953)
Authors: Lei Yuk , Chen Luqiu , Wang Ying , Nair Lekha , Molinero Luciana , Theriault Betty , Bartman Caroline , Chong Anita , Alegre Maria-Luisa 
Published: January 2023

Abstract
The microbiota is known to influence local and systemic immune responses. To test whether the microbiota can modulate the strength of an alloresponse, we used a minor mismatched (H-Y) skin transplant mouse model in both germ-free (GF) and antibiotic-pre-treated (Abx) mice. Abx mice showed a marked reduction in bacterial diversity of their intestinal and skin flora. Skin allograft survival more than doubled in either GF or Abx mice compared to controls and colonization with a complex microbial community from conventional mice was sufficient to restore faster rejection kinetics in GF mice. Mechanistically, CFSE-labeled CD4+ anti-H-Y Marilyn T cells displayed a decrease in proliferation following in vivo adoptive transfer into Abx hosts as well as after in vitro culture with antigen presenting cells from Abx mice. Together, these data indicate decreased priming of allogeneic T cells when the diversity of resident bacterial communities is diminished. This effect is not due to a reduction in bacterial load but rather a loss of taxon-specific host-microbe interactions. This study illustrates the profound systemic effects of the microbial environment in transplant recipients and points to the microbiota as a potential therapeutic target for enhancing graft acceptance.
The expansion and activity of myeloid-derived suppressor cells in nasopharyngeal carcinoma mediated by up-regulating COX-2 (TUM6P.964)
Authors: Li Jiang 
Published: January 2023

Abstract
The expansion of myeloid-derived suppressor cells (MDSCs) is linked to tumor metastasis, but the molecular mechanism related to this link remains unclear. Here, we investigated the interactions between MDSCs and tumor cells in patients with nasopharyngeal carcinoma (NPC) and demonstrated that NPC cells induced the expansion of tumor-induced MDSCs (T-MDSCs); in turn T-MDSCs enhanced NPC cell migration and metastasis. Up-regulation of tumor cyclooxygenase-2 (COX-2) expression positively correlated with the expansion of MDSCs in NPC patients and both of COX-2 and MDSCs were poor predictors for disease-free survival. In vitro, knockdown of COX-2 expression in TW03 cells hampered T-MDSC induction by blocking IL-6. In addition, T-MDSCs promoted NPC cell proliferation, invasion and migration by triggering the epithelial-mesenchymal transition (EMT) on cell-to-cell contact; furthermore, T-MDSCs enhanced tumor lung metastasis in nude mice. Interestingly, T-MDSCs-mediated EMT was through enhancing COX-2 expression and activating the b-catenin/TCF4 pathway in NPC cells; Blockage of TGFb and iNOS significantly abolished the T-MDSC-mediated up-regulation of COX-2 and EMT in NPC cells, whereas the administration of TGFb and L-arginine supplements up-regulated COX2 expression and the b-catenin/TCF4 pathway in NPC cells. Taken together, these findings unveil a pivotal role for COX-2 in the development and cancerous contributions of MDSCs in NPC.