bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective autophagy of Bcl10 modulates T cell receptor activation of NF-κB (121.16)
Authors: Schaefer Brian , Kashyap Anuj , Paul Suman 
Published: January 2023

Abstract
The adaptor protein Bcl10 is a critically important mediator of T cell receptor (TCR)-to-NF-κB signaling. Bcl10 can be degraded by TCR-dependent proteolysis, but the molecular mechanism of degradation is poorly understood. We show that TCR engagement triggers the degradation of Bcl10 in primary effector T cells, but not in naïve T cells. TCR engagement promotes K63-polyubiquitination of Bcl10, causing Bcl10 and its signaling partner Malt1 to associate with the autophagy adaptor protein, p62. Confocal microscopy shows that cytosolic aggregates of Bcl10, Malt1, and p62 also co-localize with the autophagosome membrane protein, LC3. Biochemical analysis shows that LC3 co-precipitates in a TCR-dependent manner with Bcl10 and p62, but not with Malt1. Inhibition of autophagosome formation prevents Bcl10 degradation, leading to long-term association between Bcl10 and Malt1. Thus, the physical separation of Bcl10 and Malt1 is a direct consequence of Bcl10 autophagy, and the autophagy of Bcl10 is a highly selective process. Finally we show that inhibition of Bcl10 autophagy enhances TCR activation of NF-κB. Together, these data demonstrate that selective autophagy of Bcl10 is a homeostatic mechanism that modulates TCR signaling to NF-κB in effector T cells. To our knowledge, our data represent the first example of selective autophagy as an intrinsic homeostatic mechanism modulating a signaling cascade.
STAT5 controls Tfh development (121.19)
Authors: Nurieva Roza , Podd Andrew , Chen Yuhong , Alekseev Andrei , Wang Junmei , Dong Chen , Wang Demin 
Published: January 2023

Abstract
Recent work has identified a new subset of CD4+ T cells named as T follicular helper (Tfh) cells that are localized in germinal centers and critical in germinal-center formation. Tfh cell differentiation is regulated by IL-6 and IL-21, possibly via STAT3 factor, and Bcl6 is specifically expressed in Tfh cells and required for their lineage specification. In current study, we characterized the role of STAT5 in developmental regulation of Tfh cells. We found that a constitutively active form of STAT5 effectively inhibited Tfh differentiation by suppressing the expression of Tfh-associated factors CXCR5, c-Maf, Bcl6, Batf and IL-21, whereas STAT5 deficiency greatly enhanced Tfh differentiation. In addition, deletion of STAT5 in CD4+ T cells in vivo resulted in enhanced development of Tfh cells and germinal center B cells, and led to an impairment of B cell tolerance, suggesting that STAT5 signaling controls the humoral immunity. This knowledge may help us to find ways to treat antibody-mediated autoimmune diseases.
CD1d expression and NKT cells in a haploinsufficiency model of NF1 (121.20)
Authors: Liu Jianyun , Gallo Richard , Khan Masood , Renukaradhya Gourapura , Brutkiewicz Randy 
Published: January 2023

Abstract
Neurofibromin 1 (NF1) is a tumor suppressor gene encoding a Ras GTPase that negatively regulates Ras signaling pathways. Mutations in NF1 are linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia (JML) and Watson syndrome. CD1d-dependent natural killer T (NKT) cells play an important role in anti-tumor immunity. We have shown that CD1d-mediated antigen presentation is regulated by cell signaling pathways. To study whether a haploinsufficiency in NF1 would affect CD1d-mediated activation of NKT cells, we analyzed the NKT cell population as well as CD1d expression levels from NF1+/- mice. Our results suggest that NF1+/- mice have similar levels of NKT cells as WT littermates. However, but interestingly, CD1d expression on BMDCs from NF1+/- mice was found to be lower than those from WT littermates. There was also a slight but statistically significant decrease in the splenic B220+CD1dhi population from NF1+/- mice. On the other hand, NF1+/- mice survived better than WT littermates when challenged with a T-cell lymphoma in vivo. NKT cells from NF1+/- mice were found to be more responsive to CD1d-mediated antigen presentation in vitro, which may partly explain the increased antitumor activity observed in NF1+/- mice. In conclusion, our data suggest that NF1 plays a role in negatively regulating CD1d-mediated activation of NKT cells, and this is translated in enhanced antitumor activity in mice with a haploinsufficiency in NF1.
Choline Acetyltransferase-Expressing T cells are rare in young mice (122.7)
Authors: Olofsson Peder , Rosas-Ballina Mauricio , Ochani Mahendar , Lu Ben , Chavan Sangeeta , Diamond Betty , Tracey Kevin 
Published: January 2023

Abstract
Neural circuits regulate cytokine production to prevent potentially damaging inflammation. A prototypical vagus nerve circuit, the inflammatory reflex, inhibits tumor necrosis factor production in spleen by a mechanism requiring acetylcholine signaling through the α7 nicotinic acetylcholine receptor on macrophages. Nerve fibers in spleen lack the machinery necessary for acetylcholine production. Instead, an acetylcholine-producing, memory phenotype T cell relays the neural signal. These choline acetyltransferase+ (ChAT+) T cells are required for inhibition of cytokine production by vagus nerve stimulation. Thus, action potentials originating in the vagus nerve regulate T cells, which in turn produce the acetylcholine required to control innate immune responses. The understanding of the phenotype of ChAT+ T cells is incomplete. Using flow cytometry, we detected TCRβ+ but no TCRγδ+ ChAT+ T cells. Since acetylcholine-producing T cells are memory cells, we hypothesized that this relay function is acquired, and investigated the splenic ChAT+ T cell population early in life. Indeed, splenic ChAT+ T cells were rare in 2 to 25 days old mice (2%±0.3 of ChAT+ cells) while B cells constituted the majority of the ChAT+ splenocytes (86±5%). In contrast, frequencies of ChAT+ T cells varied considerably in adults and could constitute 1/4 of the ChAT+ population. The infrequency of ChAT+ T cells early in life suggests that the inflammatory reflex may be impaired in young mice.
Th17/Th1 axis polarization is mediated by IL-1 receptor in type 1 diabetes murine model (123.13)
Authors: Carlos Daniela , Bonfá Giuliano , Ramos Simone , Cunha Fernando , Cardoso Cristina , Ryffel Bernhard , Silva João 
Published: January 2023

Abstract
Introduction: Autoimmune diseases including type 1 diabetes (T1D) are thought to have a Th1/Th17 bias, but the underlying mechanisms driving the differentiation and activation of these pathogenic T cells has been investigated. Recently, the IL-1beta has been shown to regulate Th17 cell differentiation through of the expression of the transcription factor RORγt. Objective: For this reason, we addressed the respective IL-1 receptor (IL-1R) role in the TD1. Methods: IL-1R deficient mice and their wild-type (C57BL/6) were inoculated intraperitoneally with 40mg/Kg of streptozotocin for 5 consecutive days. Blood glucose levels and body weight were monitored weekly. The pancreatic lymph nodes (PLN) were removed to assess the Th17 and Th1 frequency by flow cytometry. Results: Diabetic IL-1R deficient mice developed lower hyperglycemia with only 50% of mice becoming diabetic. In agreement, mice lacking IL-1R have reduced inflammatory infiltrate (insulitis) and augmented insulin content into pancreatic islets by second week. In addition, the IL-1R deficiency caused a decrease in IL-17 and IFN-γ-producing CD4+ T cell population in pancreatic lymph nodes (PLN). The IL-17, IL-6, TNF-α, IFN-γ levels were not altered, but IL-10 and IL-4 levels were higher in pancreatic tissue of diabetic IL-1R deficient mice. Conclusion: These results suggest that IL-1receptor promotes the Th17/Th1 skewing in the PLN and possibly contributes to pancreatic islet damage during the T1D onset.
The T cell response to interleukin 10 alters cellular dynamics and paradoxically promotes CNS autoimmunity (123.16)
Authors: Geiger Terrence , Liu Xin , Alli Rajshekhar , Steeves Meredith , Nguyen Phuong , Vogel Peter 
Published: January 2023

Abstract
IL10 is a critical anti-inflammatory cytokine, deficiency of which leads to spontaneous autoimmunity. Yet therapeutically administered or ectopically expressed IL10 may either suppress or promote autoimmunity. Distinct lineage-specific activities may explain these contradictory effects. To dissect the T cell-specific response to IL10 during organ-specific autoimmunity, we generated mice with a specific deletion of IL10Rα in T cells and analyzed its impact in experimental allergic encephalomyelitis (EAE). Surprisingly, the T-cell response to IL10 increased EAE severity. This did not result from altered T cell functional potential; T cell cytokine profile and migratory capacity were preserved. IL10 diminished the proliferation of T cells in situ, both at the site of induction and within the target organ, actions that should restrain disease. However, this decreased proliferation was not associated with diminished cell numbers. IL10 acted cell autonomously to sustain the autoreactive T cells essential for immunopathogenesis, promoting their accumulation and distorting the regulatory and effector T cell balance. Therefore T cell specific actions of IL10 can support autoimmune inflammation, and this appears to result from an overall increase in the long term fitness of pathologic T cells. Lineage-restricted, disease-promoting activities of IL10 should be considered in its therapeutic application.
Absence of CD28 promotes development of severe thyrocyte epithelial cell hyperplasia and proliferation (TEC H/P) in IFN-γ-/- NOD.H-2h4 mice (123.20)
Authors: Kayes Timothy , Mullen Helen 
Published: January 2023

Abstract
60-70 % of IFN-γ-/- NOD.H-2h4 mice given NaI in their drinking water for 6-7 mo develop TEC H/P, a CD8-mediated thyroid specific autoimmune disease characterized by uncontrolled TEC proliferation, lymphocytic infiltrates, autoantibody production, and fibrosis, resulting in destruction of TEC and loss of thyroid function. CD28-/- IFN-γ-/- NOD.H-2h4 mice develop very severe TEC H/P at an accelerated rate with nearly 100 % of CD28-/- IFN-γ-/- NOD.H-2h4 mice developing severe TEC H/P 5-8 weeks after exposure to NaI. Thyroids have extensive fibrosis and severe TEC H/P correlates with low serum T4 levels. CD8+ T cell numbers are increased in thyroid, LN, and spleen, and CD8 cells highly express PD-1 and NKG2D. CD28-/- IFN-γ-/- NOD.H-2h4 mice have extensive lymphocyte infiltrates in salivary glands and pancreatic islets, and a few develop diabetes at 4-6 mo of age. CD28-/- IFN-γ-/- NOD.H-2h4 mice with TEC H/P have reduced numbers of peripheral FoxP3+ T reg compared to IFN-γ-/- NOD.H-2h4 mice with TEC H/P. In mice with severe TEC H/P, thyroids from CD28-/- IFN-γ-/- NOD.H-2h4 mice have reduced numbers of FoxP3+ T reg compared to IFN-γ-/- NOD.H-2h4 mice. The accelerated development of TEC H/P in CD28-/- IFN-γ-/- mice may be a result of reduced T reg number or function as preliminary data indicates that development of TEC H/P in CD28-/- IFN-γ-/- NOD.H-2h4 mice is inhibited by transfer of FoxP3+ T reg from CD28 sufficient IFN-γ-/- NOD.H-2h4 mice.
Overexpression of β-catenin in dendritic cells from type 1 diabetes patients and NOD mice may drive induction of T cells involved in β-cells destruction (123.34)
Authors: Alard Pascale , Zirnheld Arin , Parnell Sarah , Kosiewicz Michele 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is characterized by the destruction of insulin producing β-cells in the pancreas mediated by IFNγ+ T cells. Non-obese diabetic (NOD) mice and T1D patients share similar characteristics of disease progression and the immune defects associated with disease, e.g., their dendritic cells (DC) produce elevated levels of pro-inflammatory cytokines such as IL-12, a cytokine that drives differentiation of IFNγ+ T cells. We have identified a new defect in DC in NOD mice, i.e., an abnormal accumulation of the transcription factor, β-catenin, which appears to be associated with the production of pro-inflammatory cytokines. Moreover, we found that DC isolated from T1D patients also expressed elevated levels of β-catenin compared to healthy individuals. To examine the function of β-catenin in DC, we either transfected human or murine DC with β-catenin siRNA or cultured them with an β-catenin inhibitor, and found that the production of pro-inflammatory cytokines (IL-12, IL-6, TNF) and subsequent production of IFNγ by T cells added to the DC culture was abrogated. Finally, treatment of NOD mice with an β-catenin inhibitor delayed onset and decreased incidence of disease. These data suggest that elevated expression of β-catenin in T1D may regulate the pro-inflammatory cytokine production in DC that subsequently drives induction of β-cell destroying T cells. Manipulation of β-catenin may, therefore, be a novel strategy for preventing and/or treating T1D.
Conditional deletion of tumor necrosis factor receptor-associated factor 6 (TRAF6) in medullary thymic epithelial cells leads to the development of classical autoimmune hepatitis in mice (123.40)
Authors: Bonito Anthony , Aloman Costica , Fiel Maria , Danzl Nichole , Alexandropoulos Konstantina 
Published: January 2023

Abstract
Autoimmune hepatitis (AIH) is an enigmatic disease in which loss of tolerance towards self-antigens is suspected among the causes; animal models are limited, however. TRAF6 is an important signaling adaptor protein that plays a critical role in T cell tolerance by regulating medullary thymic epithelial cell (mTEC) development. mTECs in turn regulate central tolerance by ectopically expressing self-antigens and eliminating autoreactive T cells during development. In this report, conditional knockout mice lacking TRAF6 expression in thymic epithelial cells (TRAF6ΔTEC) were generated using FoxN1-cre transgenic mice (FoxN1 expression is confined to mTECs). TRAF6 deletion inhibited mTEC development and the production of mature mTECs in the thymus. This correlated with spontaneous liver-specific autoimmunity and pathognomonic features of chronic autoimmune hepatitis including interphase and lobular hepatitis, T cell and plasma cell infiltration, elevated serum transaminases and IgG, and production of anti-nuclear autoantibodies against the livers of TRAF6ΔTEC animals. A significant increase in fibrosis was also detected in TRAF6ΔTEC mice compared to littermate controls. Our data indicate that mTECs play an intrinsic role in central tolerance, and their depletion leads to AIH. This model of spontaneous AIH represents an exciting new tool to investigate autoantigen-specific T and B cell responses and regulatory mechanisms underlying the disease.
New Mouse Models for Immunological Research at The Jackson Laboratory (124.14)
Authors: Merriam Jen , Lutz Cathleen , Rockwood Stephen , Sasner Michael , Donahue Leah 
Published: January 2023

Abstract
The Jackson Laboratory Mouse Repository continues to add to a broad and varied collection of mutant mouse models that are applicable to a variety of research fields and human disease studies. Among the more recent arrivals are a number of humanized strains that are particularly suited for transplantation work, mutations helpful in unraveling the causes of autoimmunity and processes of inflammation, as well as strains that may lead to better understanding of immune cell maturation, recruitment, trafficking and function. Please stop by for an updated list of available strains or visit our website at: http://jaxmice.jax.org/research/immunology/index.html . Donating a strain to the Repository fulfills the NIH’s requirements for sharing of mice. Researchers wishing to have strains considered for inclusion in the Repository are encouraged to submit their strains at: http://www.jax.org/donate-a-mouse .
Antibodies generated against conserved antigens suppress allergic airway disease (125.13)
Authors: Stefanov Emily , Kin Nicolas , Dizon Brian , Kearney John 
Published: January 2023

Abstract
There has been a sharp rise in allergic asthma and asthma-related deaths in the developed world. The hygiene hypothesis proposes that excessively sanitary conditions early in life result in autoimmune and allergic phenomena because of a failure of the immune system to receive proper microbial stimulation during development. Chitin, a biopolymer of N-acetyl glucosamine (GlcNAc), is produced by many allergen-bearing organisms including: fungi, the exoskeleton of insects, crabs, shrimp and parasitic nematodes. We demonstrate that antibodies generated against chitin and other conserved bacterial polysaccharides, induced by neonatal vaccination or passive transfer, are reactive with and dampen the immune response against chitin and Aspergillus fumigatus. In the presence of anti-polysaccharide antibodies, we observed a marked reduction in antigen uptake, cell influx, cellular activation, and cytokine production, resulting in a striking decrease in the severity of allergic airway disease in mice. Our results suggest that antigen exposure, during the neonatal period, from environmental sources, self-antigens, or vaccination, have dramatic effects on the adult B cell repertoire and subsequent antibody responses, modulating the immune response to potential allergens later in life and thus dampening development of allergic airway disease. We propose an adjunct hypothesis that antibodies may contribute to the mechanism of protection proposed by the hygiene hypothesis.
Methylation patterns of COX-2 promoter affect gene transcription and PGE2 levels post-bone marrow transplant (126.23)
Authors: Domingo-Gonzalez Racquel , Huang Steve , Moore Bethany 
Published: January 2023

Abstract
Alveolar macrophages (AM) and polymorphonuclear leukocytes (PMN) are critical for innate immune host defense and the function of these cells is impaired post-syngeneic bone marrow transplant (BMT) due to overproduction of prostaglandin E2 (PGE2). The rate limiting enzyme for PGE2 synthesis is cyclooxygenase-2 (COX-2). This study sought to learn why COX-2 and PGE2 levels were elevated post-HSCT. Our studies show COX-2 transcription is increased in BMT AMs relative to control AMs. This is associated with hypomethylation of the COX-2 gene near the transcription start site and into exon 1. Treatment of primary AMs or MHS cells with 5-aza-2’-deoxycytidine increased COX-2 transcription and PGE2 synthesis. Transfection of MHS cells with in vitro methylated COX-2 promoter-driven constructs decreased luciferase activity relative to transfection of unmethylated constructs. Our results demonstrate COX-2 expression is highly regulated by DNA methylation. Furthermore, hypomethylation of the COX-2 gene occurs post-BMT and this correlates with increased expression of COX-2 and PGE2 in AMs from BMT mice. Thus epigenetic changes in COX-2 likely impair innate immune defense in the lung post-BMT. Our current studies suggest that transforming growth factor β may be one factor which regulates these epigenetic changes post-BMT.
Role of PAMPs and DAMPs in Graft Rejection (126.6)
Authors: Chain Robert , Varghese Linda , Gallucci Stefania 
Published: January 2023

Abstract
Dendritic cells (DCs) induce immunity or tolerance depending on the presence of danger signals. LPS is a danger signal with multiple effects on DCs, besides activation. Unpublished results from our lab show that LPS induces DC death in vitro and in vivo. It has also been reported that DCs treated with LPS during their development remained immature and induced T cell anergy. LPS triggers TLR4, a PRR also stimulated by endogenous danger signals, like HMGB1, released during tissue damage. We used a mouse transplant model to determine the effects of simultaneous exposure to LPS and endogenous danger signals, released during engraftment, on DC functions and graft survival. We used the single minor male-specific H-Y antigen mismatch. We transplanted skin of male C57BL/6 mice onto syngeneic female recipients. We administered 4 i.p. injections of 12.5ug/mouse of LPS or PBS every other day. Control mice rejected male skin graft in 24-34 days, as expected, while mice treated with LPS did not reject the graft until 64 days or later. Studying the DCs migrating out of the graft, we found a sharp decrease of DCs 48 hours post transplant and the DC loss was more severe after LPS. LPS also decreased the number of DCs with high surface expression of MHC class II. These findings suggest that the combination of endogenous danger signals released during engraftment and LPS are either killing the DCs or preventing them from maturing thus allowing for tolerance of the male skin graft.
IFNγ production by donor-reactive memory CD4 T cells is required for CD40-independent induction of pathogenic alloantibody (126.8)
Authors: Gorbacheva Victoria , Ayasoufi Katayoun , Fan Ran , Yu Hong , Valujskikh Anna 
Published: January 2023

Abstract
Donor-reactive memory CD4 T cells are potent inducers of alloantibody (alloAb) even in the absence of the CD40/CD154 pathway. The goal of this study was to determine the cytokine requirements for CD40-independent help by memory CD4 T cells. Using donor-specific TCR transgenic T cells, we found that Th1 and Th17 memory CD4 T cells elicited high titers of alloAb in CD40-/- heart allograft recipients while Th2 cells failed to do so. The resulting anti-donor Abs differed in their specificity and the ability to mediate heart allograft pathology. Compared to Th1 cells, Th17 memory cells induced inferior Ab responses against donor MHC class I molecules. Anti-donor alloAb induced by Th1, but not by Th17 memory cells, caused diffuse C4d deposition in the graft capillaries. Blocking IFNγ in CD40-/- heart allograft recipients containing memory CD4 T cells drastically reduced serum IgG alloAb titers. In contrast, donor-reactive CD8 T cells were efficiently activated under these conditions indicating that the help for CD8 T cells is IFNγ-independent. Our data suggest that IFNγ secreted by donor-reactive memory CD4 T cells not only determines donor-reactive Ab isotypes, but also influences alloAb specificity and can thus affect allograft pathology.
Adenosine A2B receptor signaling in antigen presenting cells suppress anti-tumor adaptive immune responses (127.10)
Authors: Cekic Caglar , Linden Joel 
Published: January 2023

Abstract
Adenosine is generated in response to cellular stress such as hypoxia and inflammation and acts as a “metabokine” to modulate immune responses and prevent tissue damage. The accumulation of high levels of adenosine in tumors activates adenosine A2A and A2B receptors on immune cells to attenuate tumor rejection. Previously, we have shown that A2BR blockade inhibits growth of syngeneic tumors by enhancing innate and adaptive immune responses. However, the cellular targets that mediate inhibition of tumor growth after A2B receptor blockade are unknown. In this study, we tested the activity of innate and adaptive immune cells isolated from bladder or melanoma tumors grown in mice reconstituted with mixed bone marrows from A2BR-/- and A2BR+/+ animals. While A2BR deficiency did not influence the activation of NK cells and T cells, A2BR-/- antigen presenting cells were activated more than A2BR-/- cells. Selective deletion of A2BRs on myeloid cells or CD11c expressing cells significantly delayed the growth of syngeneic melanoma. The results show that antigen-presenting cells are direct cellular targets for tumor growth inhibition after A2BR blockade. The results of this study have important implications for therapeutic use of A2B receptor blockade or deletion for treatment of cancer.