bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exercise prior to pregnancy enhances Treg-mediated suppression and reduces asthma severity in offspring in a mouse model of asthma (166.25)
Authors: Kunz Hawley , Lowder Thomas 
Published: January 2023

Abstract
We have previously shown that exercise significantly reduces airway hyperresponsiveness (AHR) and Th2 inflammatory cytokines in the lung while significantly enhancing regulatory T cell (Treg)-mediated in vitro suppression and in vivo expression. Others have shown that OVA-treated nursing dams confer protection against AHR and inflammation to pups exposed to an OVA-driven model of asthma. In the present study, we wanted to determine if exercise prior to pregnancy conferred the same effect. Male pups from exercise-trained (E) or sedentary (S) female mice were OVA-sensitized and challenged. While not significant, we saw a decrease in AHR in E pups compared to S pups. When co-cultured with CD4+CD25- effector cells, Tregs from E pups reduced proliferation from 8.4 to 10% at increasing titers, demonstrating an enhanced suppression in vitro. We saw a significant increase in the percentage of CD4+ thymocytes in the pups from E mice compared to S mice (95.1 +/- 2.7, 83.95 +/- 3.7, respectively), with a significant decrease in percent of CD8+ splenocytes and mediastinal lymph node (MLN) cells. Although not significant, there was a more than doubling of CD4+FoxP3+ thymocytes in E versus S pups. There was a trend (p=0.08) for higher CD4+FoxP3+ MLN in S compared to E pups. We show for the first time that exercise prior to pregnancy can confer protection against asthma in an OVA-driven mouse model.
Obesity compromises the ability of skin γδ T cells to regulate skin homeostasis and barrier function (166.6)
Authors: Jameson Julie , Costanzo Anne , Taylor Kristen 
Published: January 2023

Abstract
Within the epidermis of the skin resides a unique population of γδ T lymphocytes that play key roles in skin homeostasis and wound repair. During obesity and related metabolic disease the skin-resident γδ T lymphocytes become dysfunctional due the chronic inflammatory environment. This dysfunction contributes to the non-healing wounds associated with disease. We are now investigating how skin γδ T cell dysfunction impacts normal keratinocyte homeostasis. Interestingly, in lean mice we have determined that the number of keratinocytes in the epidermis is directly proportional to the number of closely neighboring γδ T cells. Once obesity and related metabolic disease ensues, the keratinocyte numbers resemble areas that are devoid of γδ T cells in lean mice and keratinocytes are unable to maintain normal homeostatic numbers. Furthermore, keratinocytes in obese mice exhibit diminished proliferation and accelerated differentiation. This results in a dysregulated epidermis in which fewer basal keratinocytes express the proliferation marker keratin 5 and more exhibit early expression of the differentiation marker keratin 1. Additionally, skin γδ T cells downregulate CD103 in obese mice, while keratinocytes alter expression of its ligand E-cadherin. Together these studies demonstrate that dysfunctional γδ T cells in the epidermis of obese mice contribute to impaired keratinocyte homeostasis ultimately resulting in compromised skin barrier function.
Rip2 plays a critical role in regulating intestinal inflammation (166.8)
Authors: Zaki Md. , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Human inflammatory bowel disease (IBD) constitutes a major health problem in developed countries. Genome wide association studies suggested that mutation in a gene encoding the intracellular pathogen sensor NOD2 is a predisposing factor for development of IBD. However, not all IBD patients exhibit the NOD2 mutation. This leads to postulate that genes downstream of NOD2 could also be mutated in some IBD patients. Upon activation by bacterial cell wall component muramyl dipeptide, NOD2 activates NF-kB and MAP kinase pathways through adaptor molecule RIP2. However, the role of RIP2 in IBD pathogenesis has not been examined yet. Therefore, we studied the role of RIP2 in intestinal inflammation using a mouse model of colitis induced by dextran sulphate sodium (DSS). We observed that both Nod2-/- and Rip2-/- are susceptible to DSS-induced colitis, however, more pronounced disease phenotypes developed in Rip2-/- mice manifested by increased weight loss, diarrhea, rectal bleeding and exacerbated histological changes compared to wild-type and Nod2-/- mice. Investigation on the nature of the immune response suggests that certain cytokines critical in IBD pathogenesis are differentially regulated in Rip2-/- mice as compared to Nod2-/-. These novel findings underscore the divergent role Rip2 play in maintaining intestinal homeostasis and protecting intestinal inflammation, and may open new avenues in the understanding of IBD pathogenesis.
Egr-2 regulates inflammatory plasticity of effector T cells (167.1)
Authors: Raymond Meera , Wang Ping 
Published: January 2023

Abstract
Effector CD4 T cells can orchestrates different immune cells to induce a protective immune response, but a disregulated response can result in immune pathology or autoimmune diseases. Therefore, the levels of activation and the production of effect cytokines have to be controlled. In addition to the extrinsic regulation of effector T cells by Treg, Early Growth Response 2 gene (Egr-2) has been found to regulate T cell tolerance intrinsically. Egr-2 deficiency in T cells results in the development of autoimmune diseases. We have found that Egr-2 is a negative regulator for the expression of pro-inflammatory cytokines. In the absence or over expression of Egr-2, T cells have normal effector function such as proliferation and production of IL-2 and IFNg. However, the production of IL-17 and differentiation of Th17 cells were reciprocally regulated in the presence or absence of Egr-2 in CD4 T cells. The disregulation of Th17 was associated with severity of the EAE in these mice suggesting that Egr-2 is important for the control of inflammatory plasticity of the effector T cells. We have discovered that Egr-2 interacted with Batf a transcription factor from AP1 family and suppressed its function. Batf partially represses AP1 activation, but activates IL-17 expression and Th17 differentiation. These findings conclude that Egr-2 controls Th17 mediated inflammation at least partly through inhibition of Batf function.
MicroRNAs (miR16 and miR146a) regulation of lupus development in NZB/W F1 mouse model (167.11)
Authors: Yuan Yao , Kotenko Serguei , Laurindo Fernanda , Salerno Erica , Raveche Elizabeth 
Published: January 2023

Abstract
SLE is a heterogeneous autoimmune disease and the specific cause remains unknown. IFNα has well defined positive effects in lupus disease development and by delivering exogenous IFNα to NZB/W F1 mouse accelerated lupus manifestations. Yet the effects of IFNλ, sharing partially common signaling pathways with IFNα, remains unknown in lupus. In the study, we treated B/W mice with IFNα or IFNλ for 12 week period and IFNα treated group developed much earlier and more severe lupus-disease than others. Moreover, combination with both cytokines enhanced the effects of either single treatment. At the time when only IFNα treated group developed proteinuria, this group of mice showed a pronounced decrease in regulatory B cells (B10)than others, in contrast, IFNλ treated group showed an expansion of B10. Furthmore, we wanted to investigate whether or not, as consequences of IFNs treatment, any specific microRNAs could be responsible for the cell type changes. In these B/W mice, splenic RNA were taken for microRNA microarray analysis. Results showed a few miRNAs up or downregulated in IFNs treated groups. To validate the result, miR16 and miR-146a were selected for realtime PCR.We found that almost in consistence with microarray, IFNλ treated had elevated level of both miRNAs than control, however, IFNα treated group showed underexpression of both miRNAs. Thus, it is likely that abnormal miRNAs changes due to IFNs treatment may drive the disease development in the lupus-prone B/W mice.
Induction of tolerance in the NOD mouse by WE14, a peptide of Chromogranin A (167.14)
Authors: He Jing , Delong Thomas , Bradley Brenda , Haskins Kathryn 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease mediated by autoreactive T cells. We recently reported that a new autoantigen, chromogranin A (ChgA), is targeted by diabetogenic T cell clones in the NOD mouse (Stadinski, Delong et al, Nat Immunol 2010). To investigate the induction of antigen-specific tolerance by WE14, a natural proteolytic cleavage product of ChgA, we tested whether this peptide could protect against adoptive transfer of diabetes in the NOD mouse model. Our data indicate that the production of inflammatory cytokines is less in both CD4 and CD8 T cells from NOD mice after WE14 immunization. Furthermore, co-transfer of spleen cells from NOD mice immunized with WE14 delayed disease transfer by spleen cells from diabetic NOD mice. We also demonstrated that when the WE14 peptide is coupled to antigen-presenting cells (APCs) by a chemical cross-linker, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (ECDI), transfer of disease into NOD recipients by the pathogenic Th1 T cell clone BDC-2.5 was totally prevented. These results suggest that WE14 may be a tolerogenic peptide in T1D. We are currently investigating the mechanism of this antigen-specific tolerance through analysis of T cells from the pancreas after adoptive transfer.
Fas and p21 suppress autoimmunity by regulating cell cycle progression of effector/memory T cells (167.19)
Authors: Balomenos Dimitrios , Daszkiewicz Lidia , Vazquez-Mateo Cristina 
Published: January 2023

Abstract
Fas drives activated T cell apoptosis in vitro, but lymphadenopathy and lupus development in Fas-deficient (lpr) mice cannot be explained only on the basis of the lpr T cell apoptotic defect. Unexplained also remains the in vivo hyperproliferation of T cells in lpr mice, including CD4+, CD8+ and CD4-CD8-TCR+ cells. To date, the effect of lpr T cell-hyperproliferation in both lymphadenopathy and lupus autoimmunity is not known. We investigate this point by generating T cell-specific p21-trangenic -lpr mice. p21, a cell cycle inhibitor and a lupus-like autoimmunity suppressor, regulates the expansion of memory but not of naïve T cells. p21 overexpression in lpr T cells did not affect primary T cell responses, but profoundly diminished lpr T cell proliferation after secondary activation, without affecting the compromised apoptotic cell death of lpr T cells. Importantly, in vivo, p21 overexpression restrains lpr T cell memory expansion, and results in reduced autoantibody production, glomerulonephritis and lymphadenopathy in lpr mice. p21 overexpression did not affect T cell memory in wt mice, pointing to a specialized role for p21 in hyperproliferating T cells. Overall we conclude that lpr T cell hyperproliferation is essential for the increased T cell memory, the autoimmunity and the lymphadenopathy development in lpr mice. Thus, decreasing the hyperproliferation of pathogenic T cells may be of therapeutic value for both Lupus and the Autoimmune Lymphoproliferative Syndrome.
α9β1 integrin-mediated signaling serves as an intrinsic regulator of pathogenic Th17 cell generation (167.2)
Authors: Kanayama Masashi , Morimoto Junko , Matsui Yutaka , Yoshida Toshimichi , Uede Toshimitsu 
Published: January 2023

Abstract
Th17 cells are recognized as primary pathogenic cells in autoimmune disorders such as rheumatoid arthritis. The differentiation of Th17 cells are tightly regulated by cytokines derived from APCs, receiving various signals including toll-like receptor (TLR) stimuli. Previously, we have reported that the interaction between matricellular proteins such as tenascin-C (TN-C) and osteopontin (OPN) and α9 integrin was capable of inducing the several cytokines from synovial cells, result in the development of arthritis. In this study, we have used collagen induced arthritis (CIA) model and found that increased numbers of α9 integrin positive conventional dendritic cells (cDCs) and macrophage were detectable in draining lymph node (dLN) shortly following first immunization, and these cells produced both TN-C and OPN. Alpha9 integrin-mediated signaling, induced by TN-C and OPN, enhanced Th17-related cytokine productions including IL-6 by cDCs and macrophages in synergy with TLR2 and 4 signaling, results in the promotion of Th17 generation at dLN. Moreover, Th17 cells, generated under blocking of α9 integrin-mediated signaling showed low level of CCR6 expression and impaired migration ability toward CCL20. In fact, the functional blockade of α9 integrin ameliorated the development of CIA. Thus, we have identified α9 integrin-mediated signaling by TN-C and OPN as a novel intrinsic regulator of pathogenic Th17 cell generation that contributes to the development of autoimmune arthritis.
Cross-regulation between TLR7, TLR8, and TLR9 in autoreactive B cells. (167.22)
Authors: Green Nathaniel , Debatis Michelle , Marshak-Rothstein Ann 
Published: January 2023

Abstract
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies against intracellular targets, frequently nucleic acid associated proteins. Toll-like receptors (TLR) 7 and TLR9 (which recognize single stranded RNA and DNA respectively) have been shown by our lab to be critical in the activation of autoreactive B cells. Genetic deletion of TLR7 significantly reduces disease, whereas genetic removal of TLR9 leads to exacerbated disease. To understand the basis for this difference, we examine the in vitro responses elicited by DNA- and RNA-containing immune complexes (ICs). TLR9-/- autoreactive B cells respond more strongly than TLR9+/+ B cells to RNA ICs, however TLR7-/- and TLR7+/+ autoreactive B cells respond comparably to DNA ICs. Since it has been shown that TLR7 mediated responses can significantly increase with a two-fold change in expression, we examined whether the absence of TLR9 changed the expression levels of TLR7, or vice versa. While TLR7 and TLR9 expression were unaffected by the absence of the other TLR, TLR7 knockout B cells expressed greatly enhanced levels of TLR8, which is thought to be suppressive. In fact, TLR7-/- B cells show a repressed response to DNA ICs in the presence of TLR8 ligands. This inhibitory effect of TLR8 on TLR9 mediated responses in TLR7 knockouts could partially explain the dramatically decreased disease seen in TLR7 deficient autoimmune prone mouse models.
Aicda mediates central tolerance in B cells (167.24)
Authors: Kuraoka Masayuki , Holl T. , Liao Dongmei , Womble Mandy , Kelsoe Garnett 
Published: January 2023

Abstract
Activation-induced cytidine deaminase (AID), the product of Aicda gene, is required for somatic hypermutation (SHM) and class-switch recombination (CSR) of immunoglobulin genes. Although crucial for humoral immunity, these processes exact genomic damage that often results in cell death, and occasionally oncogenesis. In mice, AID expression, SHM and CSR are thought to be restricted to mature B cells in germinal centers. We reported that developmentally immature B cells in mice and humans express low levels of AID, which support limited SHM and CSR. However, the physiological significance of AID expression and activity in these B-cell compartments is controversial. Here we show that low levels of AID in immature mouse bone marrow B cells suppress the development of autoreactivity. Aicda deficient mice exhibit significantly increased serum autoantibody and reduced capacity to purge autoreactive immature/transitional B cells; the clonal deletion and heavy chain receptor editing characteristics of autoimmune 3H9 VDJ knock-in mice is significantly impaired in the absence of AID expression. In vitro, AID deficient immature/transitional B cells are more resistant to anti-IgM induced apoptosis than their normal counterparts. Thus, early AID expression in immature B cells plays a fundamental and unanticipated role in purging self-reactive B cells during their development in the bone marrow. We are currently investigating signals that induce AID expression in immature B cells in vitro.
Trp53 negatively regulates autoimmunity via the STAT3-Th17 axis (167.27)
Authors: Cui Yan , Zhang Shuzhong , Zheng Mingquan , Kibe Ryoko , Huang Yunping , Marrero Luis , Zieske Arthur , Iwakuma Tomoo , Kolls Jay 
Published: January 2023

Abstract
Emerging evidence suggests that the tumor suppressor p53 is also a crucial regulatory factor for many physiological processes. Previous observations indicate that p53 negatively regulates inflammation via suppressing inflammatory cytokine production by antigen presenting cells. However, the role of p53 in regulating autoimmune effector T cells, such as IL-17 producing Th17 cells, is largely unknown. Here, we demonstrate that p53nullCD45.1 mice spontaneously develop autoimmunity associated with a significant increase in Th17 cells in their lymphoid and pathological tissues as well as elevated levels of inflammatory cytokines IL-6 and IL-17 in serum. This increase in Th17 response results largely from an increased sensitivity of p53nullCD45.1 T cells to IL-6 induced STAT3 phosphorylation. Administration of a STAT3 inhibitor to p53nullCD45.1 mice reduced the frequency of Th17 cells and alleviated autoimmune pathology. This is the first report, to our knowledge, revealing the contribution of T-cell p53 in the suppression of autoimmunity by controlling Th17 differentiation. This study suggests that p53 serves as a guardian of proper immunological functions and that the p53-STAT3-Th17 axis might be a therapeutic target for autoimmunity.
Negative feedback regulation of encephalitogenic Th1 cells by IFNγ in experimental autoimmune encephalomyelitis (167.28)
Authors: Sestero Christine , Naves Rodrigo , Singh SimerPreet , De Sarno Patrizia , Raman Chander 
Published: January 2023

Abstract
Ifngr1-/- mice develop more severe experimental autoimmune encephalomyelitis (EAE) with delayed onset compared to wild-type (WT) mice. Enhanced disease severity in Ifngr1-/- mice was associated with elevated numbers of both Th1 and Th17 cells in the central nervous system. Elevated Th17 population was expected, but the expanded numbers of Th1 cells in Ifngr1-/- mice contradicts the paradigm that IFNγ signaling is a positive feedback loop for Th1 expansion. Furthermore, cultures of encephalitogenic T cells isolated from these mice restimulated under Th1 skewing conditions contained several fold greater numbers of IFNγ-expressing Th cells than WT T cell cultures. These observations led us to investigate the possibility that IFNγ participates in a negative feedback loop associated with Th1 differentiation. Addition of suboptimal levels of neutralizing anti-IFNγ mAb during in vitro polarization of encephalitogenic WT T cells to Th1 cells led to at least a two-fold greater number of CD4+IFNγ+ T cells. Suboptimal neutralization of IFNγ didn’t alter the generation and/or expansion of Th1 cells when encephalitogenic T cells were obtained from Ifngr1-/- or Stat1-/- mice, confirming the requirement for intact IFNγ signaling. Contrary to the traditional dogma, these data suggest that IFNγ can negatively regulate Th1 differentiation, which may partly explain the opposing biology of IFNγ in EAE and multiple sclerosis.
CD5 modulates regulatory T cell function, proliferation, and survival. (168.12)
Authors: McGuire Donald , Sestero Christine , De Sarno Patrizia , Raman Chander 
Published: January 2023

Abstract
We previously showed that CD5-/- mice develop less severe experimental autoimmune encephalomyelitis (EAE). This is unexpected since CD5-/- T cells are hyperresponsive to myelin peptide immunization. The decreased severity is partially due to loss of CD5-dependent survival signals that are mediated by the activation of the serine/threonine kinase CK2. EAE in CD5 mutant knock-in mice (CD5ΔCK2BD), in which the ability to bind/activate CK2 is abrogated, was also less severe and recapitulates the findings in CD5-/- mice. CD5-/- Treg cells are hypersuppressive in in vitro suppression assays and therefore may also contribute to lower EAE severity in the CD5-/- mouse. This led us to address if CD5 regulates Treg cell function through activation of CK2. In contrast to the hypersuppressive activity of Treg cells from CD5-/- mice, Treg cells from CD5ΔCK2BD mice were less efficient in their ability to suppress responder CD4+ T cells than WT Treg cells. The proliferation of CD5-/- Tregs in response to stimulation with anti-CD3 in the presence of APCs and IL-2 was greater than WT and CD5ΔCK2BD. From these results we infer that the CD5-dependent CK2 activation pathway is a positive regulator of Treg suppressive activity. In contrast, the inhibitory (ITIM) domain is a negative regulator of Treg biology and proliferation. The combined signaling pathways from these two domains of CD5 balance Treg function and maintain homeostasis.
Controlling viral immunoinflammatory lesions by modulating aryl hydrocarbon receptor signaling (168.19)
Authors: Veiga Parga Tamara , Suryawanshi Amol , Rouse Barry 
Published: January 2023

Abstract
Ocular HSV-1 infection can cause a blinding CD4+ T cell orchestrated immunoinflammatory lesion called Stromal Keratitis (SK). Lesion severity is affected by the balance of proinflammatory effector T and regulatory T cells (Treg). In this report we show that expanding Treg activity using TCDD (2, 3, 7, 8- Tetrachlorodibenzo-p-dioxin), a ligand for the AhR receptor, results in the differential expansion of Treg in the eye and a resultant reduction in the extent of inflammatory lesions. Treatment of HSV infected mice with TCDD either on day 1 or day 5 pi, diminished the severity of SK lesions as well as the extent of corneal angiogenesis. The observed effect was mainly due to the changed balance of CD4+ T cells in the cornea that were IFN-γ or IL17 cytokine producers compared to those that were Foxp3+ Tregs. The change was explained by the significantly increased apoptosis of activated effector T cells but not of Tregs. Additionally, effector T cells from HSV infected mice proliferated significantly less in TCDD treated mice compared to control mice. Furthermore the addition of TCDD to the culture of antiCD3/CD28 stimulated naïve CD4+ T cells caused significant induction of Tregs. In conclusion, our results demonstrate that modulation of AhR signaling by TCDD represents a valuable approach to expand Treg and inhibit Th1 and Th17 cells to control HSV induced blinding lesions.