bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporally-defined inflammatory pathways modulate distinct mechanisms of effector and regulatory CD4 T cell responses. (P1189)
Authors: Thompson Lucas , Lai Jen-Feng , Valladao Andrea , Thelen Tennille , Urry Zoe , Ziegler Steven 
Published: January 2023

Abstract
Potentially autoreactive T cells are controlled by both cell-intrinsic and dominant trans-suppressive mechanisms. One of the major mediators of dominant suppression of immune responses are regulatory CD4+ T cells that express the transcription factor Foxp3. These cells can arise during thymic T cell development or be induced in the periphery from naïve CD4+ T cells. The factors that drive development of induced regulatory T cells can represent a critical choice for health or autoimmunity in the case of potentially self-reactive CD4 T cells. Numerous studies have implicated a role for enhanced effector differentiation and suppressed induction of regulatory T cells in response to antigen in the context of inflammatory signals. Here we show that inflammatory stimuli can drive expansion of functional Foxp3+ regulatory T cells in vivo, largely driven by type I interferon signals. Furthermore, naïve CD4+ T cells that are bystander-activated by interferon in the absence of cognate antigen exhibit tolerance, reduced effector function, and enhanced induction of Foxp3 upon subsequent antigen encounter. These data suggest that transient bystander activation imposes a dynamic state of responsiveness in naïve CD4+ T cells, in which the nature of subsequent differentiation is shaped by temporal coordination of antigen/TCR and inflammatory signals. This work provides an interesting new framework for potential antigen-specific therapeutic immunization strategies.
Role of Foxo3 transcription factor in the susceptibility to central nervous system autoimmunity (P1127)
Authors: Dejean Anne , Stienne Caroline , Carrié Nadège , Saoudi Abdelhadi 
Published: January 2023

Abstract
Foxo proteins control gene expression during many cellular processes including cell cycle progression, reactive oxygen species detoxification, survival and death. During viral infection, we demonstrated that Foxo3 critically down-regulates the magnitude of the anti-viral T cell response by constraining the production of key inflammatory cytokines by dendritic cells (DCs). This impact on the innate immune response suggests that Foxo3 is likely to control the intensity of the adaptive immune response irrespective of its nature. We therefore analyze the implication of Foxo3 in the susceptibility to central nervous system inflammation. We showed that mice deficient in Foxo3 are remarkably resistant to experimental autoimmune encephalomyelitis (EAE), a common mouse model for multiple sclerosis. We showed that the reduced severity to EAE of Foxo3 deficient mice is not the consequence of an impaired priming of CD4 T cells in response to immunization. Rather, Foxo3 appears to play a role in the regulation of Th17 and Th1 differentiation. Thus, the reduced severity of EAE in Foxo3 deficient mice may be related to the inability of Foxo3-deficient CD4 T cells to differentiate into encephalogenic T cells. By dissecting the cellular mechanism involved in this phenotype, we showed that Foxo3 plays crucial role in both DC and T cells. Understanding Foxo3 function will bring new insights into the mechanisms that support immune cell homeostasis during normal and pathologic immune responses.
A role for inactivation of the Foxo1 transcription factor in the differentiation of T follicular helper cells (P1131)
Authors: Stone Erica , Pepper Marion , Katayama Carol , Yang Edward , Goldrath Ananda , Crotty Shane , Hedrick Stephen 
Published: January 2023

Abstract
We have previously shown that mice with a T cell-specific deletion of Foxo1 develop autoimmunity due to reduced Foxp3+ regulatory T cell development and function. These mice also have an increased percentage and absolute number of CXCR5+PD1+ T follicular helper (TfH) cells, a T cell subset that is able to help B cells, and this may help to explain how high levels of auto-antibodies develop in mice in which Foxo1 is specifically deleted from T cells. However, it was unclear if the large number of TfH cells is due to a cell intrinsic role for Foxo1 in restricting TfH differentiation or more indirectly the result of inflammatory autoimmunity. We now report that activated Foxo1-deficient CD4 T cells more readily differentiate into TfH cells. This increased differentiation into TfH cells occurs despite reduced expression of ICOS, a key molecule leading to TfH differentiation, in the absence of Foxo1. Furthermore, Foxo1-deficient CD4 T cells can differentiate into TfH cells in the absence of ICOS signaling. Additionally, ICOS stimulation rapidly decreases Foxo1 protein levels in activated CD4 T cells suggesting a negative feedback control mechanism. In conclusion, our data strongly suggest that ICOS signaling serves to inactivate Foxo1 in the differentiation of TfH.
The role of innate immune adaptor STING in suppressing lupus (P4070)
Authors: Sharma Shruti , Schattgen Stefan , Chan Jennie , Huyler Annie , Rothstein Ann , Fitzgerald Katherine 
Published: January 2023

Abstract
The ability of innate immune receptors such as the TLRs to sense both microbial products and self-molecules released from stressed, damaged or dying cells is well accepted. The discovery of TLR-independent DNA/RNA sensing pathways raises the possibility that additional mechanisms besides TLRs regulate self-DNA/RNA driven autoimmune diseases such as systemic lupus erythematosus (SLE). Both TLR-dependent and independent pathways lead to the induction of type I IFNs, which can promote autoimmunity. Here, we examined the role of a key inducer of type I IFNs, the cytosolic DNA-sensing stimulator of interferon genes (STING) pathway in SLE pathogenesis. We generated STING-/- mice on a lupus prone MRL/lpr background and compared disease progression to lpr/lpr littermates. Unexpectedly, STING/lpr mice display accelerated onset and progression of disease. These animals display gross increases in lymphocytic and plasma cell populations, class-switched Abs and exacerbated nephritis. Significant expansion of the myeloid compartment is concomitant with increases in serum cytokines TNF-α and IFNγ. Further analysis of STING/lpr mice shows a surprising increase in anti-SmRNPs, RNA specific Abs and an interferon stimulated gene (ISG) signature. Given the central role of type I IFNs and TLR7 in MRL/lpr pathogenesis, and the increases we see in ISGs and anti-RNA Abs, we propose an unprecedented role for STING in limiting lupus pathogenesis by regulating TLR and type I IFN signaling pathways.
Gene analysis of brain in aged-experimental autoimmune encephalomyelitis mice reveals over-expression of stress response pathway-related genes (P4104)
Authors: Seo Ji-Eun , Hasan Mahbub , Sarma Sailendra , Kang Min-Jung , Jung Byung-Hwa , Cho Mi-La , Nam Suk Woo , Park Won Sang , Kim Ho-Youn , Kwon Oh-Seung 
Published: January 2023

Abstract
Experimental autoimmune encephalomyelitis (EAE) is the most common animal model of multiple sclerosis. In our previous works, two different age groups of mice (6 weeks; Y vs. 15 months; O) were used to compare the severity of EAE. Significant decreases of body weight and increases of clinical score were observed in O-EAE, indicating a more severe form of disease was induced at old age. With the purpose to identify genes that contribute to this pathology, we investigated gene expressions in brain using gene microarray. As a result, 32 genes including MHC class II molecules antigen, complement component and lysozyme in Y-EAE, and 4 genes including circulatory system, cell adhesion and migration functions in O-EAE were up-regulated compared to their controls. Expression of 44 genes was significantly different between O-EAE and Y-EAE. O-EAE showed 27 up-regulated genes with related pathways including response to stress and acute inflammatory responses, and 17 down-regulated genes with related pathways including immune development, hemopoiesis and homeostatic process, compared to Y-EAE. Over-expression of the stress response pathway-related genes in O-EAE such as argine vasopressin, cyclin-dependent kinase inhibitor 1A and hypoxia-induced factor 3α were validated by qRT-PCR. Our data suggest that the highly expressed genes related to stress responses in O-EAE affected serious disease process, and these genes may be prior targets for susceptibility of EAE.
Shared and distinct immunogenetic pathways in myocarditis and type 1 diabetes (P4108)
Authors: Lv HuiJuan , Smith Ross , Shankar Jyotsna , Lipes Myra 
Published: January 2023

Abstract
The transgenic expression of the human type 1 diabetes (T1D) susceptibility allele, HLA-DQ8, in I-Aβ-/- NOD - but not in C57BL/6 - mice results in fatal autoimmune myocarditis. We have found that mortality from myocarditis in each of three lines of DQ8+NOD mice paralleled the incidence of T1D in the corresponding DQ8+/-I-Ag7+/-NOD lines, indicating that these two disease processes, although clinically distinct, share common DQ8-mediated pathways. To study the impact of non-MHC T1D susceptibility genes on myocarditis development, we crossed our highest-incidence myocarditis line with congenic NOD.B6 Idd3/B10 Idd5 mice that are protected from insulitis and T1D, and NOD.B10 Idd9 mice that develop insulitis but no T1D. The DQ8+NOD.Idd3/5 mice harbored the expected B10-derived splice variant of CTLA-4 (Idd5.1) and were strongly protected from myocarditis with a mortality of 9% (3 of 35 mice) compared to 80% in control mice (33 of 41 mice; P &lt; 0.0001), and the majority of DQ8+NOD.Idd3/5 mice showed normal heart histology. In contrast, the Idd9 locus had minimal impact on myocarditis, with similar mortality in DQ8+NOD.Idd9 and control mice. These results show that susceptibility to myocarditis arises from the combined effects of MHC and non-MHC genes, some of which are shared with T1D. Since the human homologue of the Idd5.1 locus confers increased risk for human T1D and other autoimmune diseases, these findings have implications for the pathogenesis of human myocarditis.
MicroRNA-146a acts as a guardian of the quality and longevity of hematopoietic stem cells (P4467)
Authors: Zhao Jimmy , Rao Dinesh , O'Connell Ryan , Baltimore David 
Published: January 2023

Abstract
During inflammation and infection, hematopoietic stem and progenitor cells (HSPCs) are stimulated to proliferate and differentiate into mature immune cells, especially of the myeloid lineage. MicroRNA-146a (miR-146a) is a critical negative regulator of inflammation. Deletion of miR-146a produces effects that appear as dysregulated inflammatory hematopoiesis, leading to a decline in the number and quality of hematopoietic stem cells (HSCs), excessive myeloproliferation, and, ultimately, to exhaustion of the HSCs and hematopoietic neoplasms. In the absence of miR-146a, LPS-mediated serial inflammatory stimulation accelerates the effects of aging. The chronic inflammatory stress on HSCs in deleted mice involves a molecular axis consisting of upregulation of TRAF6 leading to excessive activity of NF-κB and overproduction of the cytokine IL-6. At the cellular level, we show that the defects are attributable to both an intrinsic problem in the miR-146a-deficient HSCs and extrinsic effects of miR-146a-deficient lymphocytes and non-hematopoietic cells. This study has identified a microRNA, miR-146a, to be a critical regulator of HSC homeostasis during chronic inflammatory challenge in mice and has provided a molecular connection between chronic inflammation and the development of bone marrow failure and myeloid malignancies. This may have implications for human hematopoietic malignancies, such as myelodysplastic syndrome, which frequently displays downregulated miR-146a expression.
New implications of ADAMs in TNFα related diseases: ADAM10 deficient B cells exhibit increased ADAM17 and TNFα (P4388)
Authors: Folgosa Lauren , El Shikh Mohey , Conrad Daniel 
Published: January 2023

Abstract
ADAM10 is required for the development and maintenance of proper secondary lymphoid tissue architecture and optimal Ig class-switching; however, the underlying mechanisms remain unclear. TNFα is cleaved by ADAM10 and ADAM17; and, the aberrant lymphoid tissue architecture noted in B cell specific ADAM10 deficient mice (ADAM10B-/-) resembles that of global TNFα knockouts prompting analysis of TNFα production in these mice. Our results indicated that ADAM10B-/- B cells stimulated with LPS/IL4 or anti-CD40/IL4 showed increased levels of soluble and membrane bound TNFα compared to WT, which was confirmed by qPCR and immunohistochemistry of naïve lymph nodes. In addition, ADAM17 expression, assessed by qPCR, was increased in stimulated ADAM10B-/- B cells, suggesting ADAM17 overcompensation. In contrast, stimulated ADAM10B-/- B cells exhibited impaired proliferation and activation as indicated by decreased 3H-thymidine incorporation and less B220 upregulation respectively. We reason that ADAM17 overcompensation generates aberrant TNFα signaling and enhanced TNFα expression in stimulated ADAM10B-/- B cells; however, other ADAM17 substrates may be involved and are currently under investigation. In conclusion, this work institutes a key interplay between ADAM10, ADAM17, and B cell-TNFα with critical implications in autoimmune pathogenesis and therapeutics where deliberate inhibition of one ADAM may be accompanied by upregulation of another, resulting in unintended consequences.
Human B cell development in a novel xenograft model that provides selective TSLP and IL-7 stimulation (P4390)
Authors: Milford Terry-Ann , Su Rui-jun , Baez Ineavely , Francis Olivia , Zhang Xiaobing , Payne Kimberly 
Published: January 2023

Abstract
IL-7 is critical for mouse B cell development and available data suggest that TSLP has overlapping functions. Our previous in vitro studies show that IL-7 expands human B cell progenitors by ~60 fold (JI 2009 82:4255). Our recent experiments provide evidence that TSLP similarly expands human B cell progenitors in vitro and that primary human bone marrow stroma provides an in vivo source of both cytokines. To study interplay between IL-7 and TSLP in early stages of in vivo human B cell lymphopoiesis, we developed a novel xenograft model system that selectively provides IL-7 and/or TSLP stimulation. While mouse IL-7 can act on human cells, TSLP is species-specific. To overcome this obstacle we coupled a xenograft model system engineered to provide human TSLP (hTSLP) with IL-7 neutralizing antibodies. Preliminary data obtained using this model system transplanted with cord blood CD34+ cells shows that the production of B cell precursors is reduce by ~90% in mice that lack both IL-7 and hTSLP stimulation as compared to mice where both are present. The absence of hTSLP stimulation, alone, reduced B cell production by about 50%, while the effects due IL-7 neutralization, alone, were about half this. These data suggest that IL-7 and TSLP play an essential and at least partially overlapping role in human B cell development. Current studies are aimed at defining the differential stage-specific effects of TSLP and IL-7 on survival and proliferation of human B cell progenitors in vivo.
Cellular characterization of V cell populations (novel antigen specific immunoglobulin expressing cell lineage) from immunized mice (P4402)
Authors: Elia Jeanne , Chronopoulou Efthalia , Uribe-Benninghoff Alejandro , Rabenstein Jacob , Nguyen Andrea , Fisher Janean , Berry Jody 
Published: January 2023

Abstract
In our efforts to improvemonoclonal antibody production, we identified novel populations of antigen-specific cells which can be classified as neither a B cell, nor an Eosinophil using classical surface markers. One novel antigen specific population is identified by the phenotype CD49b+/IgG+/IgE+/B220- (IgG/E V-cell). Immune animals have identifiable IgG/E V cell populations in multiple tissue sites including bone marrow, spleen, and blood. No IgG/E V cells were detected in the lymph nodes, thymus, or peritoneal cavity. The percentages of IgG/E V cells differ in each of the positive tissue compartments tested. Higher levels of IgG/E V cells are routinely seen in blood compared to bone marrow or spleen of immune animals. These cells have been sorted and successfully cultured on several attempts. Supernatants from sorted V cell populations were assayed for cytokine and immunoglobulin production via CBA sandwich immunoassay. No soluble IgG was detected, but low levels of IL-4 and TNF were.
A pre-BCR/NFκB pathway suppresses STAT5-dependent pre-B cell leukemia (P4408)
Authors: Katerndahl Casey , Heltemes-Harris Lynn , Willette Mark , Ramsey Laura , Koeuth Thearith , Baechler Emily , Farrar Michael 
Published: January 2023

Abstract
Mice expressing a constitutively active form of STAT5b (called Stat5b-CA mice) develop pre-B leukemia with low frequency (~1-2%). Microarray analysis of these leukemias shows decreased expression of genes involved in pre-BCR signaling. Stat5b-CA mice crossed to mice with defects in a coherent signaling pathway downstream of the pre-BCR involving BLNK, BTK, or PKCβ developed pre-B leukemia in &gt; 75% of progeny. These leukemias exhibited reduced expression of a subset of NFκB target genes, which was important for transformation as Stat5b-CA x Nfkb1-/- mice also developed pre-B leukemia. Our results point to an unexpected role for NFκB1 as a tumor suppressor in pre-B cells. We found that STAT5 cooperates with defects in this pre-BCR-dependent pathway to repress expression of the potential tumor suppressor genes Foxo1, Foxo3a, Ikzf1, and Ikzf3. Our findings demonstrate that STAT5 activation antagonizes a pre-BCR-dependent pathway that limits pre-B cell proliferation, promotes pre-B cell differentiation, and inhibits pre-B cell transformation.
B cell transcription factors define a novel tumor suppressor gene network in acute lymphoblastic leukemia (P4410)
Authors: Farrar Michael , Heltemes Harris Lynn , Kornblau Steven , Larson Jon , Starr Tim , Largaespada David 
Published: January 2023

Abstract
We recently found that STAT5 activation correlates with poor response to therapy in B-ALL. To identify genetic defects that cooperate with STAT5 activation to initiate transformation we carried out a forward genetic screen involving the mutagenic transposon Sleeping Beauty. This screen identified a number of cooperating partners including gain-of-function mutations in Sos1 and loss-of-function mutations in Ebf1 and Ikzf1 (i.e., Ikaros). Haploinsufficiency of Ebf1 or the related transcription factor Pax5 synergized with STAT5 to rapidly induce progenitor B-ALL in 100% of mice. The leukemic cells displayed reduced expression of Ebf1 and Pax5, which affected a small subset of EBF1 or PAX5 target genes, including tumor suppressor genes and oncogenes. To test whether compound haploinsufficiency of Ebf1 and Pax5 alone is sufficient to cause transformation, we generated Ebf1+/- x Pax5+/- mice. Over 80% of these mice developed progenitor B-ALL. We observed similar results in Ebf1+/- x Ikzf1+/-, Pax5+/- x Ikzf1+/-, and Pax5+/- x Ebf1+/- x Ikzf1+/- mice; interestingly, although most leukemias were B-ALL we also observed T-ALL suggesting that T-All may arise from a B cell progenitor. Our findings suggest a model in which STAT5 activation cooperates with small perturbations in a self-reinforcing network of transcription factors critical for B cell development to initiate ALL and that loss of any two alleles in the network results in a loss of network tumor suppressor function.
Ikaros directly upregulates transcription of B lineage-specific genes in human B cell leukemia (P4412)
Authors: Dovat Sinisa , Song Chunhua , Payne Kimberly 
Published: January 2023

Abstract
Ikaros encodes a DNA-binding protein that functions as a master regulator of hematopoiesis and a tumor suppressor in pre-B acute lymphoblastic leukemia (B-ALL). Loss of Ikaros function is associated with impaired hematopoiesis and high-risk B-ALL in humans. The mechanism of Ikaros tumor suppressor activity is unknown. Using quantitative chromatin immunoprecipitation (qChIP) we demonstrate that Ikaros binds to the promoters of genes required for B cell differentiation in primary leukemia cells. Luciferase reporter assays demonstrated that Ikaros activates transcription of these B lineage-specific genes. Increased expression of Ikaros via retroviral transduction in B-ALL cells resulted in increased transcription of these critical B cell differentiation genes, as well as increased binding of Ikaros to their promoters. The inhibition of Casein Kinase II (CK2) resulted in dephosphorylation of Ikaros and enhanced Ikaros-mediated transcriptional activation of the B lineage-specific genes in B-ALL. Treatment of the pre-B ALL cell line, Nalm6, with a CK2 inhibitor, resulted in increased Ikaros binding to the promoters of B lineage genes, increased transcription of B cell differentiation genes, and cell cycle arrest. Results suggest that Ikaros functions as a positive regulator of B cell differentiation by directly upregulating the transcription of B lineage-specific genes in B-ALL. The presented data suggest that CK2 has a critical role in B cell differentiation and in leukemogenesis.
The thymic hypoplasia common to 22q11.2 deletion syndrome patients is linked to a deficiency of several novel RNA species (P4448)
Authors: Hoover Ashley , Eitson Jennifer , Kahn Shaheen , Ratliff Lyndsay , Cleaver Ondine , de la Morena M. Teresa , van Oers Nicolai 
Published: January 2023

Abstract
22q11.2 deletion syndrome (22qDS) is the most frequent chromosomal microdeletion syndrome in humans (1 /4000 births). It arises from erroneous interchromosomal exchanges during meiosis, resulting in a hemizygous microdeletion of ~60 genes (3Mb) and 4 microRNAs on chromosome 22. Sixty percent of 22qDS patients have a thymic hypoplasia, resulting in a peripheral T cell lymphopenia. The thymic hypoplasia, hypoparathyroidism, and cardiac anomalies originate from defective pharyngeal pouch development during embryogenesis. The molecular causes remain unresolved. We profiled the RNA species in thymic tissues from normal and 22qDS patients. The miR-200 family and miR-205 were deficient in the 22qDS samples. MiR-205 is localized within a long intergenic non-coding RNA (lncRNA). This lncRNA and three transcription factors, Pax1, Foxn1, and Foxg1, were severely under-expressed in those 22qDS patients with a thymic hypoplasia. The functional role of these RNAs is being addressed with viral knockdown approaches in fetal thymic organ and pharyngeal pouch explant cultures. Preliminary findings suggest a role for several of these RNAs in thymic and parathyroid tissue specification. Results from our study could lead to better therapies for reconstituting T cell development in patients undergoing stem cell transplants and chemoablative therapies and for the elderly, who have a loss of thymic epithelial tissue with diminished T cell output.