bluuebunny/crossref_metadata_2025_split huggingface dataset:
Signaling through the TNF-R2 (p75) but not TNF-R1 (p55) is absolutely required for in vivo CTL maturation in parent-into-F1 mice. (34.4)
Authors: Soloviova Kateryna , Puliaeva Irina , Lang Tom , Puliaev Roman , Via Charles 
Published: January 2023

Abstract
The transfer of B6 splenocytes into normal BDF1 mice results in donor cytotoxic T lymphocytes (CTL) that eliminate host B cells by two weeks and is a useful model of in vivo CTL generation. We previously demonstrated that in vivo anti-TNF mAb treatment prevents CTL and B cell elimination, shifting disease phenotype to a lupus-like disease. To determine if TNF acts directly on naïve donor T cells or whether TNF acts indirectly to promote CTL, we transferred p55 and/or p75 TNF-R defective or wild type (WT) B6 donor cells into WT F1 hosts. At two weeks after transfer host splenocyte populations were assessed by flow cytometry. P55-&gt;F1 mice exhibited host B cell elimination comparable to WT-&gt;F1 mice (~10% of control F1 values) whereas p75 and p55/p75-&gt;F1 mice exhibited a significant increase in host B cells (&gt;150% control) consistent with CTL failure and lupus-like disease. Host DC (CD11c+) and macrophage (CD11b+) values paralleled those of B cells for p55 or p75-&gt;F1 mice. Compared to WT-&gt;F1 mice, peak day 7 serum IFN-g was significantly reduced only for p75-&gt;F1 mice. Defective elimination of host populations in p75-&gt;F1 mice was not due to failure of donor CD8 T cells to engraft or to express an effector phenotype (CD44hi, CD62Llo). These results support the conclusion that TNF signaling through the p75 receptor is critical for in vivo CD8 CTL maturation in normal unirradiated mice whereas p55 signaling has a minimal if any role.
IL-10 desensitizes Th17 cells memorized with Candida antigen (34.9)
Authors: Inatsu Akihito , Jeschke Marc , Yoshida Shohei , Asai Akira , Kobayashi Makiko , Herndon David , Suzuki Fujio 
Published: January 2023

Abstract
Th17 cells are important effector cells in host resistance against C. albicans infection. Here, we demonstrated the desensitization of Th17 cells memorized with C. albicans in severely burned patients. Under stimulation with the Candida antigen, T cells with abilities to produce IL-17, to express RORγt and to be proliferative were considered to be Th17 cells memorized with Candida antigen. PBMC (2 x 106 cells/ml), isolated from burn patients (&gt; 30% TBSA burn), were stimulated with Candida antigen (heat-killed C. albicans) for 3 days. Culture fluids obtained were assayed for IL-17, and cells harvested were analyzed for expression of RORγt. The proliferative response of these PBMC stimulated with the antigen was tested by BrdU proliferation kit. In the results, as compared with healthy donor PBMC, the decreased amounts of IL-17 were produced, and RORγt was not expressed by patient PBMC. The proliferation of burn patient PBMC stimulated with the antigen was greatly decreased as compared with that of controls (326 ± 32% vs. 86 ± 15%). Burn patient serum (15%) inhibited the proliferation of healthy donor PBMC stimulated with the antigen. IL-10 was detected in burn patient serum, and burn patient serum treated with anti-IL-10 mAb did not inhibit the proliferation of Th17 cells stimulated with the antigen. These results indicate that T cells memorized with Candida antigen are desensitized in severely burned patients. IL-10 is indicated as an effector of this desensitization.
The role of cyclophilins in regulating leukocyte recruitment in chronic allergic asthma. (35.14)
Authors: Stemmy Erik , Constant Stephanie 
Published: January 2023

Abstract
Chronic allergic asthma is an airway disease characterized by persistent inflammation. Elevated numbers of eosinophils, activated lymphocytes, and mast cells, as well as increased levels of IL-5, are detectable in the airways and lung tissues of asthmatic patients even in the absence of allergen challenge. The factors regulating this persistent inflammation are not known. While classical chemokines such as eotaxins 1-3, RANTES, MIP-1α, and MCP-1 are highly elevated after acute allergen challenge, they return to baseline levels by 24h after exposure. Although better known as intracellular chaperone proteins or as the target of the immunosuppressive drug cyclosporine A, extracellular cyclophilins are also potent chemoattractants that are elevated during lung inflammation. We propose that extracellular cyclophilins could function as important chemoattractants regulating the leukocyte recruitment and persistence observed during the chronic phase of allergic asthma. To test this possibility, we made use of a mouse model of chronic asthma and inhibited the function of cyclophilins during the chronic phase of the disease using the drug NIM811, a non-immunosuppressive analog of cyclosporine A (provided by Novartis). Mice treated with NIM811 demonstrated a significant reduction (~50%) in airway and tissue inflammation upon acute allergen challenge. These findings suggest a potential role for cyclophilins in maintaining inflammation in chronic asthma.
Inhibition of T cell proliferation decreases atherosclerotic lesion size revealing a role of IL-17 in mediating aortic CD11b+CD11c+ cell accumulation (35.4)
Authors: von Vietinghoff Sibylle , Koltsova Ekaterina , Mestas Javier , Ley Klaus 
Published: January 2023

Abstract
Atherosclerosis is a chronic inflammatory disease of the artery wall with innate and adaptive immune components, however, immunosuppressive therapy is not uniformely beneficial. Mycophenolate suppresses lymphocyte proliferation by inhibiting inosine-monophosphate dehydrogenase. In this study, we tested whether mycophenolate inhibited atherosclerosis in apolipoprotein-E-deficient (Apoe-/-) mice. Apoe-/- mice treated with 30 mg/kg/day mycophenolate during 12 weeks of high fat diet showed significantly decreased aortic leukocyte infiltration. Flow cytometry at 3 and 12 weeks of high fat diet revealed significantly reduced aortic αβTCR+ cell content and reduced αβTCR+ cell proliferation as measured by BrdU incorporation. Aortic atherosclerotic lesion sizes were significantly reduced. Among T cell cytokines, IL-17 was significantly reduced in plasma of mycophenolate-treated mice. IL-17 receptor A was expressed on both blood monocytes and aortic CD11b+CD11c+ cells. Proliferation and aortic content of CD11b+CD11c+ cells and plasma levels of IL-6 and TNF-α were reduced. CD11b+CD11c+ cells in aortas of IL-17 receptor deficient mice after 12 weeks of high fat diet were significantly reduced compared to wild-type mice. Our data suggest that that mycophenolate curbs IL-17 production, which in turn limits myeloid cell accumulation in atherosclerosis. Since mycophenolate is approved for human use, this suggests its potential application for prevention and/or therapy.
Anti-inflammatory and anti-arthritic effect of essential oil isolated from Curcuma wenyujin (35.7)
Authors: Kim Hwan Mook , Kang Jong Soon , Lee Ki Hoon , Lee Chang Woo , Lee Kiho , Park Song-Kyu 
Published: January 2023

Abstract
Curcuma species has been reported to exert anti-inflammatory and anti-tumor effects. Curcuma wenyujin is mainly cultivated in wenzhou region of China and it was reported that the main constituents of Curcuma wenyujin is different from that of other Curcuma species. In this study, we investigated the effect of essential oil isolated from Curcuma wenyujin (CW) on inflammation and arthritis in rodents. CW dose-dependently suppressed lipopolysaccharide (LPS)-induced TNF-α production in mice. CW also inhibited zymosan-induced inflammation in concentration-dependent manner. Further studies demonstrated that CW attenuated the development of arthritis in adjuvant- and collagen-induced arthritis model and the anti-arthritic effect of the highest dose of CW was comparable to that of 0.1 mg/kg of dexamethasone. Collectively, the results presented in this report demonstrate that CW exerts anti-inflammatory and anti-arthritic effects. Our results suggest that CW might be a potential therapeutic agent for the treatment of inflammatory diseases, including rheumatoid arthritis.
Aicda inhibits B-cell development (36.12)
Authors: Kuraoka Masayuki , Kelsoe Garnett 
Published: January 2023

Abstract
Activation-induced cytidine deaminase (AID) is required for B lymphocytes to undergo somatic hypermutation (SHM) and class-switch recombination (CSR) in the immunoglobulin genes. Whereas AID expression, SHM and CSR are crucial for effective humoral immunity, these processes exact substantial costs in genomic damage that often result in programmed cell death and occasionally, lead to oncogenesis. In mice and humans, AID expression, SHM, and CSR are thought to be largely restricted to the mature, antigen-activated B cells in germinal centers (GC). In amphibians, birds, and some mammals, however, AID expression and activity is present both in GC B cells and in distinct subsets of developmentally immature B cells. Whether this developmentally regulated expression of AID and activity is also present in mice and humans is controversial. Here we quantify AID expression in developing mouse B cells and demonstrate its substantial effects on B lymphopoiesis. Bone marrow cells from AID deficient mice exhibit a significant advantage over normal congenic hematopoietic competitors in the production of B lymphocytes but not any other leukocytic lineage. This early lymphopoietic advantage in AID deficient cells is also manifested by an increased tempo of B-cell development. We conclude that early, developmentally regulated AID expression represents a fundamental and conserved lymphopoietic pattern that is widely distributed among the vertebrate species for diversification of immunoglobulin.
miRNAs are required for the epidermal Langerhans cell development (36.18)
Authors: Zhou Li , Wang He , Li Kai , Qi Ruiqun , Zhang Zhenggun , Weiland Matthew , Kaplan Daniel , Mi Qing-Sheng 
Published: January 2023

Abstract
Langerhans cells (LCs) are skin-resident DCs that express the C-type lectin Langerin and have a life cycle distinct from many other types of DCs. Even though LCs were first described more than 100 years ago, their development and immunological functions still remain enigmatic. MicroRNAs (miRNAs), a class of 21-25 nt single-stranded non-coding small RNAs, are increasingly being recognized as important regulators of gene expression through the inhibition of effective mRNA translation. Using Cre-loxP tissue-specific Dicer deletion, our laboratory and others have reported that deletion of miRNAs significantly affects the development and function of B, T, and NKT cells. To test the roles of miRNAs in the development of LCs, we generated a mouse strain with tissue-specific disruption of Dicer in the late stage of LC development mediated by Langerin-Cre. We found that Dicerfl/fl.langerinCre+ mice had significantly reduced number of epidermal LCs and the expression of Langerin was significantly reduced in miRNA-deficient I-Ab positive LCs. miRNA-deficient LCs have a defect on their maturation in vitro, but have normal capacity for antigen uptaking. Using BRDU staining, we found that increased both LC proliferation and apoptosis appear in Dicerfl/fl.langerinCre+ mice compared to WT mice. Thus, our findings highly suggest that miRNAs are required for the LC development and homeostasis.
Neutrophil density in bone marrow controls granulopoiesis by feedback inhibition (36.21)
Authors: Cain Derek , Snowden Pilar , Sempowski Gregory , Kelsoe Garnett 
Published: January 2023

Abstract
Normally, neutrophil pools are maintained by “steady-state” granulopoiesis. Inflammation, however, is thought to elicit growth factors that accelerate neutrophil production through a distinct developmental program known as “emergency” granulopoiesis. In IL-1RI-/- mice, adjuvant-induced emergency granulopoiesis is defective due to impaired progenitor proliferation. Interestingly, this hematopoietic defect is associated with impaired neutrophil mobilization from bone marrow (BM), raising the possibility that increased proliferation by hematopoietic progenitors is a response to reduced BM neutrophil density rather than pro-inflammatory signals. Consistent with this potential feedback mechanism, non-inflammatory depletions of mature BM neutrophils by passive antibody elicit emergency granulopoietic responses similar to those induced by adjuvant, and progenitor proliferation fluctuates inversely with BM neutrophil numbers. Furthermore, mice bearing a genetic defect in neutrophil survival exhibit constitutive emergency granulopoiesis. Whereas adjuvant potently induces serum G-CSF, a neutrophil growth and mobilization factor, neutrophil depletion elicits equally robust granulopoietic responses with substantially reduced levels of G-CSF. These observations suggest that other - perhaps unknown - factors mediate accelerated granulopoiesis, and we propose a common model for the feedback regulation of both steady-state and emergency granulopoiesis.
Dendritic cell expression of CD24 inhibits autoantigen-mediated deletion of T lymphocytes in the thymus (36.30)
Authors: Bai Xue-Feng , Liu Jin-Qing , Zhang Xuejun , Reid Hugh , Boyd Richard , Khattabi Mazin , El-Omrani Hani , Zheng Pan , Liu Yang 
Published: January 2023

Abstract
Despite negative selection, significant numbers of autoreactive T cells can be easily detected and expanded even in normal individuals. While lack of self antigen expression has been largely attributed as a key factor, we have reported that CD24, a GPI-anchored glycoprotein, regulates thymic deletion of autoreactive T lymphocytes. CD24-deficient 2D2 TCR transgenic mice (2D2+CD24-/-), whose TCR recognize myelin antigen MOG, failed to generate functional 2D2 T cells. Here we further show that elimination of MOG antigen expression in 2D2+CD24-/- mice (through creation of 2D2+CD24-/-MOG-/- mice), completely restored thymic cellularity and function of 2D2 T cells. Restoration of CD24 expression on dendritic cells, but not on thymocytes also restored 2D2 T cell generation in 2D2+CD24-/- mice. Taken together, we propose that CD24 expression on dendritic cells inhibits autoantigen-mediated deletion of autoreactive thymocytes.
A novel role of IκBα and WWOX in promoting lymphoid Molt-4 and Jurkat T cell differentiation (36.42)
Authors: Huang Shenq Shyang , Chang Nan-Shan 
Published: January 2023

Abstract
Human common fragile site gene WWOX, encoding WW domain-containing oxidoreductase (designated WWOX, FOR or WOX1), plays critical roles in the pathogenesis of cancer and maintenance of normal physiology. To explore the role of WOX1 in lymphoid cancer, here we determined that transient expression of WOX1 induced the expression of a differentiation marker CD3 in an acute lymphoblastic leukemia cell line Molt-4, but the induction was less effective in better-differentiated Jurkat T cells. Upregulation of RORγ, one of the Th17 cell markers, was shown in Molt-4, but not Jurkat T cells, overexpressing WOX1. Mapping analysis revealed that the N-terminal WW domain of WOX1 induced T lymphoid cell differentiation, in which a dominant negative and phosphorylation mutants (i.e. Y33R and Y61R) of WOX1 blocked the effect. We determined that the N-terminal WW domain of WOX1 physically interacts with IκBα (an inhibitor of NF-κB), as determined by co-immunoprecipitaiton and Fluorescence/Förster resonance energy transfer (FRET). Ectopic IκBα, via its N-terminal ankyrin-repeat region, induced Molt-4 differentiation. Both WOX1 and IκBα did not enhance T cell differentiation synergistically, suggesting that they may nullify each other’s function. In positive controls, phorbol and ionophore A23187 induced cell differentiation by upregulating IκBα, CD3 and WOX1 in Molt-4 T-cells. Together, our finding demonstrates a novel WOX1/IκBα regulatory mechanism for T-cell differentiation.
An unexpected role for the Src family kinase Blk in early T cell development (36.44)
Authors: Laird Renee , Hayes Sandra 
Published: January 2023

Abstract
Src family kinases are involved in the initiation of antigen receptor signaling, and each lymphocyte lineage expresses different family members. B cells express Lyn, Fyn and Blk, while T cells express Lck and Fyn. To determine whether there are differences in the expression of Src family kinases between αβ and γδ T cells, we used gene expression profiling and found that γδ T cells express Blk in addition to Lck and Fyn. Next, we developed an intracellular flow cytometric assay to examine Blk expression in T lineage cells. Surprisingly, we detected Blk in progenitor populations in both the thymus and bone marrow. To determine the significance of Blk expression in these progenitors, we compared T cell development in various aged blk+/+ and blk-/- mice. We found that during ontogeny the cellularity of the blk-/- thymus did not reach wild-type numbers until 4 weeks of age, whereas the cellularity of the blk-/- lymph nodes, which was always less than that of blk+/+ mice, reached a level that was not significantly different from blk+/+ mice at 5 weeks of age. Given that thymus size and output are dependent on CD25-CD44-CD4-CD8- (DN4) thymocyte proliferation, we compared the proliferation status of DN4 thymocytes from blk+/+ and blk-/- mice and noted significantly less proliferating DN4 thymocytes in blk-/- mice than in blk+/+ mice. Together, these data demonstrate that Blk is expressed in T cell progenitor populations and suggest a role for Blk in regulating thymus cellularity.
Obesity induces premature thymic involution and restricts T cell repertoire diversity (36.47)
Authors: Youm Yun-Hee , Yang Hyunwon , Vandanmagsar Bolormaa , Rood Jennifer , Kumar K.Gannesh , Butler Andrew , Dixit Vishwa 
Published: January 2023

Abstract
Yun-Hee Youm, Hyunwon Yang, Bolormaa Vandanmagsar, Jennifer Rood, K. Ganesh Kumar, Andrew A. Butler and Vishwa Deep Dixit Obesity increases risk of infections and cancer, suggesting adverse effects on immune-surveillance. Here we report that obesity compromises the mechanisms regulating T cell generation via inducing premature thymic involution. Diet-induced obesity reduced the total number of thymocytes and significantly increased apoptosis in developing T cell populations. Obesity accelerated the age-related reduction of naïve T cells and decreased T cell receptor excision circle bearing peripheral T cells, an index of recently generated T cells from thymus. Defects in thymopoiesis in obese mice were due to a reduction in the lymphoid progenitor pool and deterioration in the thymic stromal microenvironment. Interestingly, obesity also increased the frequency of thymic fibroblasts and reduced the number of thymic epithelial cells (TECs). Furthermore, the TECs of DIO mice displayed reduced expression of IL-7 and auto immune regulator (Aire) mRNA. Obesity induced via melanocortin 4 receptor (Mc4r) deficiency also constricted the T cell receptor repertoire diversity, recapitulating the thymic defects observed with diet-induced obesity. In humans, progressive adiposity with or without type-2-diabetes also compromised thymic output. Collectively, these findings establish that obesity constricts T cell diversity by accelerating age-related thymic involution.
Impairment in the strength and duration of ERK activation in Gads deficient mice (36.51)
Authors: Hassaballa Ashraf , Yankee Thomas 
Published: January 2023

Abstract
The Gads adaptor protein regulates TCR-induced calcium mobilization by mediating the interaction between SLP-76 and LAT. Gads-/- mice had a defect in the transition from double positive (DP) thymocytes to single positive (SP) cells, suggesting a role for Gads in positive and negative selection. This function of Gads was supported by crossing Gads-/- mice with TCR transgenic mice. Our goal is to understand the biochemical basis of the defect in thymic selection seen in Gads-/- mice. To address this we investigated signaling molecules upstream and downstream of Gads. First, we examined whether the magnitude and duration of TCR-dependent ERK phosphorylation in Gads+/+ and Gads-/- thymocytes. The peak level of ERK phosphorylation was reduced in Gads-/- mice, but the signal was prolonged. We then examined CD69 upregulation in vitro. In DP thymocytes, TCR-induced CD69 upregulation was comparable in wild-type and Gads-/- cells, indicating that all the DP thymocytes received TCR stimulation, even though ERK phosphorylation was reduced. To test the mechanism by which Gads might regulate ERK phosphorylation, we tested whether Gads might regulate the expression or phosphorylation of TCRζ. We found that the activation of TCRζ is impaired in Gads-/- thymocytes. We conclude that Gads regulates thymic positive selection by regulating TCRζ phosphorylation and ERK activation. This research is supported by NIH grant P20 RR016443 and American Cancer Society RSG-08-182-01-LIB.
Developmental targets of IL-7 and Flt ligand in human B cell production (36.8)
Authors: Milford Terry-Ann , Baez Ineavely , Dovat Sinisa , Payne Kimberly 
Published: January 2023

Abstract
Signals induced by IL-7 and Flt ligand (FL) are critical components of the regulatory network that governs early B cell development in mice. The role of these cytokines in human B lymphopoiesis is less clear. We previously reported that IL-7 is required for in vitro human B cell production from adult bone marrow (Parrish et al. JI 2009 182:4255). Here, we use a human-only culture model to examine the effects of IL-7 and FL, separately and together, on the production of developmental subsets of human B lineage cells from hematopoietic stem cells in cord blood. While B cell production was essentially absent in cultures without IL-7 or FL, small populations of CD19+ B lineage cells were produced with either IL-7 or FL alone. The combination of IL-7 and FL increased B cell production up to 75 fold. To identify the developmental targets of IL-7 and FL we assessed 3 subsets that include developmentally sequential populations of human B cell precursors. The production of CD19-IL-7Rα+CD34+ progenitors was dependent on FL, but not IL7, and the addition of IL-7 did not expand this population. CD34+ pro-B cells showed variable responses to both IL-7 and FL while IL-7 primarily targeted CD19+CD34- pro-B cells for expansion. The intensity of CD19 staining was approximately a log higher in all cultures with IL-7. These data suggest that FL targets CD19-CD34+IL-7Rα+ progenitors that respond to IL-7 to upregulate CD19 and then expand as CD34 is lost during human B cell differentiation.
TIPE2 serves as a molecular switch of phagocytosis during infection (37.12)
Authors: Wang Zhaojun , Johnson Derek , Sun Honghong , Gus Yael , Fayngerts Svetlana , Xue Fan , Ruan Qingguo , Chen Youhai 
Published: January 2023

Abstract
Phagocytosis is essential for host defense against microbial pathogens and clearance of apoptotic cells. TIPE2 (TNF-α-induced protein 8 like-2) is a newly described inhibitor of immune receptor signaling. We report here that TIPE2 knockout (KO) mice were resistant to lethal Listeria monocytogenes infection, cleared the bacteria more rapidly and effectively, and produced lower levels of inflammatory cytokines than wild type (WT) mice. TIPE2 KO macrophages had enhanced phagocytic activity as compared to WT macrophages. TIPE2 regulated phagocytosis at multiple steps, including internalization and phagosome maturation as well as bacteria killing. Importantly, Toll-like receptor activation dramatically downregulated TIPE2 expression while significantly enhanced phagocytic activity of macrophages. These results indicate that TIPE2 may function as a molecular switch of phagocytosis during infection. In response to pathogens, down-regulation of TIPE2 promotes phagocytosis, which in turn eliminates the pathogens.