bluuebunny/crossref_metadata_2025_split huggingface dataset:
Roles of MHC class Ia and class Ib in hsp70 mediated anti-tumor responses in the frog Xenopus (43.11)
Authors: Nedelkovska Hristina , Goyos Ana , Easterhoff David , Maggirwar Sanjay , Robert Jacques 
Published: January 2023

Abstract
The heat shock proteins (hsps) gp96 and hsp70 mediate potent antigen-dependent anti-tumor responses in both mammals and Xenopus. We have developed an adoptive cell transfer assay using peritoneal leukocytes as antigen presenting cells (APCs), and shown that hsp72, but not hsc73, is as potent as gp96 to prime T cell responses in vivo against the Xenopus thymic tumor 15/0 that is tumorigenic when transplanted in MHC-compatible Xenopus clones. The 15/0 tumor expresses several nonclassical MHC class Ib genes and β2-m, however it does not express classical MHC class Ia. Despite the lack of class Ia expression by 15/0, Xenopus adults generate potent cytotoxic CD8 T cell effectors (CCU-CTLs) that specifically recognize and kill the 15/0 tumor. We postulate that hsp72, but not hsc73, can prime class Ib-mediated anti-tumor CCU-CTL responses by interacting with APCs. To reveal the roles of class Ia and class Ib in this process we silenced surface expression of both molecules on APCs and assessed the effects in priming hsp72- or hsc73-mediated tumor immunity by adoptive transfer. To further elucidate the involvement of class Ia and class Ib in hsp70-mediated T cell function in vivo, we developed reliable transgenic techniques for our Xenopus clones and obtained F0 animals with silenced β2-m expression in vivo. This study allows us to gain better perspective into the intricate relationship between the two hsps, class Ia and class Ib molecules in T cell function as well as tumor immunity.
Neospora caninum high mobility group box-1 (HMGB1) stimulates tumor necrosis factor-alpha (TNF-alpha) production by the murine macrophage cell line RAW264.7 (43.26)
Authors: Cao Lili , Fetterer Raymond , Zhang Xichen , Tuo Wenbin 
Published: January 2023

Abstract
Neospora caninum is a protozoan parasite that causes abortion in cattle. One of the possible mechanisms by which N. caninum induces pregnancy failure is by eliciting host inflammatory responses. Two putative genes encoding the high mobility group box-1 proteins (HMGB1, 98AA) are present in the Neospora genome and have a 51% nucleic acid sequence homology. These proteins are of non-histone nuclear origin and belong to the “alarmin” family which are inducers of proinflammatory cytokines, and therefore may be involved in provoking host inflammatory responses during pregnancy. Recombinant proteins were expressed in E. coli, purified by Nickel column and treated with Polymixin B to remove endotoxin. Antibodies raised against the NcHMGB-1 detected endogenous NcHMGB1 of expected size, confirming the presence of the proteins in tachyzoites. Lysate from E. coli transfected by plasmid alone was similarly purified and used as control. The results showed that both rNcHMGB1 proteins stimulated TNF-alpha in RAW264.7 cells in a dose dependent fashion. A unrelated Neospora protein (89AA) was used as a control, but TNF-alpha was not stimulated in RAW264.7 cells by this protein. The data indicate that the NcHMGB1 is active in cross-regulating host immunity and may be involved in eliciting uncontrolled inflammatory responses which induce pregnancy failure in cattle.
Interaction of children's acetaminophen with antigen and antibody from bovine and swine albumin sources (43.8)
Authors: Vezzoli Gary , Sinclair Jennifer , Mason Charles , Brulotte Joe 
Published: January 2023

Abstract
We have conducted optical, structural, and charge transport studies of the interaction of children's strength tylenol with both antigen and antibody sources from bovine and swine albumin over the physiological temperature range. Our results show that acetaminophen is chemically and structurally stable over this temperature range and up to 108F, however, is adversely affected by low-to-moderate concentration of NaCl(aq)forming black crystallites of unestablished structure. Our charge-transport and real-time visual and optical microsocopy data indicate a strong interaction between acetaminophen and antibodies from both sources, especially swine albumin. Recovered product from these experiments show formation of various species, including sliver-shaped yellow crystals, and a multi criss-crossed channel structured species appearing near interface/boundry locations of the sample. The pronounced absence of antibody serum in the regions of acetaminophen diffusion support Czech Republic work reporting in the British Medical Journal, Lancet, October 16th 2009, that acetaminophen caused a weakening of a multi-purpose vaccine produced by GlaxoSmithKline. Our work shows that acetaminonphen interacts with bovine antigen in a non-Euclidean geometry, similar to a 3-cusp hypocycloid (deltoid). Because interaction with antigen shows an unusual time-dependent geometry, the interaction with antibodies shows long-term kinetic dependence.
α4β7 integrin is essential for contact hypersensitivity by regulating migration of T cells to inflammatory skin. (44.11)
Authors: Ohmatsu Hanako , Kadono Takafumi , Sugaya Makoto , Tomita Manabu , Kai Hiromichi , Miyagaki Tomomitsu , Saeki Hidehisa , Tamaki Kunihiko , Steeber Douglas , Tedder Thomas , Sato Shinichi 
Published: January 2023

Abstract
β7 integrin, a cell adhesion molecule, is present in the form of α4β7 integrin or αEβ7 integrin. α4β7 integrin is expressed on most leucocytes and is essential for their migration to gut-associated lymphoid tissues by interacting with its primary ligand, MAdCAM-1, which is preferentially expressed in gut-associated lymphoid tissues. Although the importance of α4β7 integrin in intestinal inflammation has been established, its role in cutaneous inflammation remains to be elucidated. Here we show that β7 integrin-deficient mice, not αE integrin-deficient mice, are defective in contact hypersensitivity (CHS) responses. β7 integrin deficiency does not affect irritant contact dermatitis. The distribution, migration, and function of antigen presenting cells from β7 integrin-deficient mice are comparable to those from wild-type mice. Moreover, sensitized β7 integrin-deficient T cells are able to respond to antigen stimuli in vitro, and elicit CHS responses when directly injected into the skin. However, they are defective in reaching the skin under inflammatory conditions, resulting in reduced CHS responses when intravenously injected. Furthermore, T cells treated with anti-α4β7 integrin neutralizing antibody elicit impaired CHS responses. These results indicate a novel role of α4β7 integrin in regulating T cell migration to inflammatory skin.
Development and Migration of Pre-Plasma Cells in the Mouse Lymph Node (44.5)
Authors: Fooksman David , Skokos Dimitris , Dustin Michael , Nussenzweig Michel 
Published: January 2023

Abstract
Plasma cells (PCs) play important roles in the acute response to infection and the long-term protection of the host by acting as antibody factories. In this study, we imaged the differentiation and migratory behavior of nascent plasma cells (PC) in lymph nodes of mice by intravital two-photon microscopy using a Blimp-1-YFP transgene. Pre-PCs differentiate in the germinal center and migrate to the medullary cords where they become sessile plasma cells. Their migration has been shown to be chemokine-dependent based on in vitro chemotaxis assays and histological sections using chemokine receptor-deficient cells. Here we identify a novel migration pattern for pre-PCs, which is unique among previously-described lymphocytes and uses an alternative pathway for motility.
Sex Differences in the Innate Immune Response to Heart-Passaged Coxsackievirus B3: Microarray Analysis (45.16)
Authors: Onyimba Jennifer , Coronado Michael , Frisancho J. , Shin Jaewook , Fairweather DeLisa 
Published: January 2023

Abstract
Recent studies have shown that innate immunity influences the progression from viral infection to autoimmunity. The incidence and severity of autoimmune disease differs between men and women, including the heart inflammatory autoimmune disease myocarditis which is increased in men. To better understand the reason for increased heart disease in men, we studied sex differences in the innate immune response to heart-passaged coxsackievirus B3 (CVB3) in BALB/c mice by microarray. Five male and female BALB/c mice were infected intraperitoneally (ip) with CVB3 and spleens harvested 12 hours (h) later during the innate immune response and compared to uninfected controls. Gene expression was determined using an Affymetrix Mouse Gene 1.0 ST Array. We found that 24 genes were significantly increased in CVB3 infected males vs. females (&gt;1.5 fold change). Androgen receptor (AR) mRNA was significantly decreased in infected males vs. infected females indicating activation of the receptor. Heat shock protein 90 (HSP90) and haptoglobin (Hp) mRNA were significantly increased in infected males vs. infected females. AR, HSP90 and Hp have been associated with increased heart disease in men. Significant gene changes were verified using qRT-PCR. Thus, we found that several genes important for the development of clinical heart disease are upregulated in males during the innate immune response. Funded in part by the Johns Hopkins University Diversity Summer Internship Program and NIH R01 HL087033.
Increased levels and function of specific T regulatory cells among rheumatoid arthritis patients that developed active tuberculosis (45.22)
Authors: Junqueira-Kipnis Ana Paula , Silva Bruna , Tannus-Silva Daniela , Ribeiro Elizangela , Rabahi Marcelo 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) patients present an autoimmune disease characterized by excessive production of TNF-α, and the treatment is based on immunosuppressant and/or anti-TNF-α therapy. In this sense, TB latent RA patients are susceptible to develop active disease. The aim of this work was to evaluate the specificity of Treg cells among TBRA patients compared to Th17 and Th1 cells. It was recruited: TB (21), RA (24) and TBRA (4) patients and 24 health controls matched by age and sex. PBMC were cultivated with M. tuberculosis antigens (ESAT-6, HSP-X, and GLcB). TBRA patients presented twice the percentage of specific Treg IL-10+ cells than TB patients (TBRA=11.1±5.1 and TB=6.1±1.5). Similar results were observed between TBRA (17.3±3.1) and TB (17.8±9.8) patients for specific Treg TGF-B+ cells. Treg cells from both TBRA and TB patients were able to reduce proliferation of autologous CD4 CFSE marked cells. M. tuberculosis specific TCD4+IFN-γ+ were similar among TB patients (6.9±1.6), and TBRA patients (5.3±1.1). TB patients presented specific Th17 cells (TCD4+ IL-17+) (3.9±1.6) as well as TBRA patients (6.2±2.4). However, RA patients showed a polyclonal activation of Th1 cells (specific=7.3±1.8, median=6.9±2.1) and, Th17 cells (specific=2.7±1.1, median= 3.3±1.5). Patients with TBRA unlike RA or TB patients presented a higher level of specific Treg and Th17 subsets. TregIL-10+ cells from TBRA individuals may be induced to control the higher levels of specific Th17 cells.
MviN mediates Francisella tularensis virulence through the inhibition of inflammasome activation. (45.5)
Authors: Ulland Tyler , Buchan Blake , Jones Bradley , Nauseef William , Sutterwala Fayyaz 
Published: January 2023

Abstract
The mechanisms by which the facultative intracellular pathogen Francisella tularensis can evade innate immunity are not well defined. We have identified a gene with homology to Escherichia coli mviN, a putative lipid II flippase, that functions as a F. tularensis virulence factor. In vivo infection of mice with a F. tularensis LVS mviN mutant resulted in improved survival and decreased bacterial burdens compared to infection with F. tularensis LVS. In vitro intracellular replication in macrophages or the ability to induce the production of TNFα or IL-6 was not effected by the mviN mutation. In contrast, we found that the mviN mutant induced increased caspase-1-dependent IL-1β secretion and cytotoxicity in macrophages compared to F. tularensis LVS. The compromised in vivo virulence associated with the mutation of mviN was dependent upon the production of IL-1β, as caspase-1-deficient mice did not exhibit preferential survival following infection. This study identifies mviN as a novel F. tularensis virulence factor through its ability to inhibit the activation of the macrophage caspase-1 inflammasome.
A rice-based oral cholera vaccine induces macaque-specific systemic neutralizing Abs but does not influence natural intestinal immunity (46.4)
Authors: Yuki Yoshikazu , Nochi Tomonori , Katakai Yuko , Shibata Hiroaki , Tokuhara Daisuke , Mejima Mio , Kurokawa Shio , Takahashi Yuko , Hatai Hirotsugu , Chubachi Aya , Nakanishi Ushio , Terao Kenji , Kiyono Hiroshi 
Published: January 2023

Abstract
We previously showed that oral immunization of mice with a rice-based vaccine expressing cholera toxin (CT) B subunit (MucoRice-CT-B) induced CT-specific immune responses with toxin-neutralizing activity in both systemic and mucosal compartments. Here, we examined whether the rice-based vaccine can induce CT-specific Ab responses in nonhuman primates. Orally administered MucoRice-CT-B induced high levels of CT-neutralizing serum IgG Abs in the 3 cynomolgus macaques we immunized. Although the Ab level gradually decreased, detectable levels were maintained for at least 6 months, and high titers were rapidly recovered after an oral booster dose of the rice-based vaccine. In contrast, no serum IgE Abs against rice storage protein were induced even after multiple immunizations. Interestingly, the macaques harbored naturally acquired intestinal secretory IgA (SIgA) Abs that were capable of reacting with CT and homologous heat-labile enterotoxin (LT) produced by enterotoxigenic E. coli (ETEC) and that had toxin-neutralizing activity. The SIgA Abs were present in macaques 1 month to 29 years old, and the level was not enhanced after oral vaccination with MucoRice-CT-B or after subsequent exposure to the native form of CT. These results show that oral MucoRice-CT-B can effectively induce CT-specific, neutralizing, serum IgG Ab responses even in the presence of pre-existing, naturally occurring CT- and LT-reactive SIgA Abs in nonhuman primates.
An Oral Bacterial-Based Diarrheal Vaccine Stimulates TGF-β-Producing Regulatory T (Treg) Cells and Confers Protection Against Experimental Autoimmune Encephalomyelitis (EAE) (47.4)
Authors: Jun SangMu , Ochoa-Rapáraz Javier , Mierzejewska Dagmara , Pascual David 
Published: January 2023

Abstract
Oral Salmonella vaccine expressing enterotoxigenic E. coli colonization factor antigen 1 (CFA/I) fimbriae induced production of Treg cells. Adoptive transfer of CD25+ Treg cells obtained from oral Salmonella-CFA/I-vaccinated mice conferred superior protection to proteolipid protein (PLP)139-151-dependent EAE to those from Salmonella vector-immunized mice; this was attributed to their differential cytokine profiles. Salmonella-CFA/I-vaccinated mice produced more TGF-β than Salmonella vector-immunized mice. To test the hypothesis Salmonella-CFA/I-induced Treg cells, independent of PLP-specificity, confers protection via TGF-β, SJL/J mice were immunized with either Salmonella-CFA/I or Salmonella vector. Two wks later, CD25+ and CD25- CD4+ T cells were sorted, adoptively transferred to naïve SJL/J mice, concomitantly treated with anti-TGF-β mAb or isotype IgG, and then induced with EAE. Mice adoptively transferred with Treg cells neutralized of their TGF-β showed earlier disease onset and greater disease severity than mice adoptively transferred with Treg cells treated with IgG control. Moreover, greater proinflammatory cytokine production was observed. This work shows Treg cells can be induced to high potency by simply vaccinating against irrelevant Ags using a live, bacterial vaccine, thus, offering a novel approach to treat autoimmune diseases independent of the auto-Ag. Supported by NIH AI-41123.
Requirement of microbiota adjuvanticity for T cell spontaneous proliferation and induction of experimental colitis (47.8)
Authors: Feng Ting , Wang Lanfang , Schoeb Trenton , Elson Charles , Cong Yingzi 
Published: January 2023

Abstract
Homeostatic T cell proliferation has been implicated in various immune-related diseases, including experimental colitis. However, little is known about how microbiota regulate T cell proliferation in lymphopenic hosts, and the role of T cell spontaneous proliferation (SP) in the pathogenesis of colitis. In this report, we show that both microbiota adjuvants and antigens are required for chronic intestinal inflammation. Microbiota ligands provide adjuvant activity to stimulate T cell SP by activating dendritic cells (DC) to produce IL-6 via a Myd88-dependent pathway. This was demonstrated by SP of adoptively transferred T cells in specific pathogen free (SPF) RAG-/- mice but not in germ-free RAG-/- mice. Reconstitution with cecal bacterial lysate-pulsed wild type DC but not with IL-6-/- or Myd88-/- DC restored T cell SP in germ-free RAG-/- mice. Adoptive transfer of CBir1 TCR transgenic (CBir1 Tg) T cells, which are specific for an immunodominant commensal bacterial flagellin antigen, induced colitis in SPF RAG-/- mice. Blockade of CBir1 Tg T cell SP by adoptive transfer of bulk OT II CD4+ T cells abrogated colitis development. Although adoptively transferred OT II T cells underwent SP in RAG-/- mice, the recipient mice failed to develop colitis due to the lack of cognate antigen in the intestinal lumen. Collectively, our data demonstrate that induction of colitis requires both microbiota adjuvant-driven T cell SP and microbiota antigen-specific T cell proliferation.
NFATc2 is an intrinsic negative regulator of proliferation in effector T cells and is necessary for extrinsic control by regulatory T cells (49.17)
Authors: Modiano Jaime , Highfill Sarah , Zhou Qing , Lewellen Mitzi , Highfill Steven , Bucher Christoph , Blazar Bruce 
Published: January 2023

Abstract
In addition to its effect to limit the number of cell division cycles and the accumulation of memory T cells, recent data suggest NFATc2 may be required to enable development and function of regulatory T cells (Tregs). Here, we verified loss of NFATc2 relieved intrinsic negative regulation: effector T cells (CD4+ /CD25-) from NFATc2 knockout (KO) mice showed more facile in vitro proliferation than effector T cells from WT or heterozygous mice and, in vivo had significantly more activated (CD69+ ) and memory phenotype (CD44hi ) T cells. In contrast, we found no differences in the number of Tregs (CD4+ /CD25+ /FoxP3+ ) between NFATc2 KO and WT mice. However, NFATc2 KO Tregs were less able to functionally suppress NFATc2 KO and WT effector cells in vitro. In contrast to NFATc2 KO Tregs, WT Tregs effectively suppressed proliferation of NFATc2 KO T cells, indicating that NFATc2 KO Tregs are hypofunctional. The reduced suppressive capacity of NFATc2 KO vs WT Tregs was not due to global T cell hyperproliferation since Tregs from Tob1 KO mice, that also have hyperproliferative T cells, were more potent suppressors than Tregs from WTs or NFATc2 KOs. The functional deficit of NFATc2 Tregs could not be replicated by treating WT Tregs with the NFAT inhibitor, cyclosporin A. Instead, Treg function was directly correlated with reduced expression of CTLA4 in NFATc2 vs WT Tregs. Our data support the premise that NFATc2 is required for Treg function, possibly by controlling CTLA4 expression.
Phosphoinositide 3-kinase p110delta isoform is essential for effective CTL responses during influenza virus infection (50.13)
Authors: Gracias Donald , Boesteanu Alina , Norton Jillian , Mueller Yvonne , Turner Martin , Katsikis Peter 
Published: January 2023

Abstract
Phosphoinositide 3-kinases (PI3K) have been known to play an important role in various functional aspects of immune cells. Class IA PI3K are heterodimers composed of a catalytic and a regulatory subunit. The catalytic isoform p110δ of class IA PI3K is preferentially expressed in hematopoietic cells and can regulate CD4+ T cells, B cells, Natural Killer and regulatory T cells. However, the role of p110δ in CD8+ T cell function has not yet been characterized. We have found that p110δ plays an important role in CD8+ T cell responses. Infection of p110δ deficient (p110δ -/-) mice with influenza virus resulted in decreased numbers of lung NP366-374- specific CD8+ T cells when compared to wild type mice (0.6±0.1x106 vs. 1.0±0.2x106, respectively, p=0.03) on day 10. To determine whether the impaired response was intrinsic to CD8+ T cells, OT-I and p110δ -/- OT-I cells were transferred into congenically mismatched recipients. These mice were infected with SIINFEKL peptide expressing influenza virus strain WSN-OVA257-264, and at day 10, lungs were harvested and analyzed for OVA257-264- specific CD8+ T cell responses. In contrast to mice transferred with control OT-I cells, those transferred with p110δ -/- OT-I cells showed a significant 5 - fold reduction in number of donor OVA257-264- specific CD8+ T cells (4.5±1.0x106 vs. 0.9±0.2x106, respectively, p=0.01). Our study shows that PI3K p110δ isoform is critical for in vivo CD8+ T cell responses.
BTLA regulates HVEM signaling in lymphocytes (50.22)
Authors: Calemine-Fenaux Jill , Hutchinson Leah , Vendel Andrew , Eaton Dan 
Published: January 2023

Abstract
The binding partner of the co-inhibitory receptor, BTLA (B and T Lymphocyte Attenuator) is the co-stimulatory receptor, HVEM (Herpes Virus Entry Mediator). We explored the biological relevance of these two opposing receptor binding partners on lymphocyte activity. Here, we report both receptors, which are endogenously expressed on primary lymphocytes, bind in a cis conformation. While BTLA is constitutively activated, HVEM does not induce its typical stimulatory response, i.e. up-regulation of NFκB signaling, in a stable co-expressing cell line. Even in the presence of the co-stimulatory HVEM ligand, LIGHT, NFκB levels remain unchanged while BTLA maintains its phosphorylation state. HVEM induced stimulatory activity was only observed in primary T cells when BTLA was neutralized with an antagonist antibody. Taken together, these data suggest BTLA is the predominant receptor of the two binding partners.
The Th17 immune response is controlled by a c-Rel−RORγ−RORγT transcriptional axis (50.36)
Authors: Ruan Qingguo , Kameswaran Vasumathi , Zheng Shijun , Wang Junmei , Liou Hsiou-Chi , Beg Amer , Chen Youhai 
Published: January 2023

Abstract
The Th17 cells utilize the retinoid-related orphan receptor-γ (Rorg) gene to specify their differentiation and lineage-specific function. However, how Rorg is switched on during Th17 differentiation is unknown. We report here that the transcription factor c-Rel drives Th17 differentiation by binding to, and activating, two distinct Rorg promoters that control RORγT and RORγ expression, respectively. Similar to RORγT, RORγ is selectively expressed in Th17 cells and is effective in specifying the Th17 phenotype. c-Rel-deficient T cells are significantly compromised in Th17 differentiation, and c-Rel-deficient mice are defective in Th17 responses, and resistant to autoimmune diseases. Thus, Th17 immunity is controlled by a c-Rel−RORγ−RORγT axis, and strategies targeting Rel/NF-κB can be effective for controlling Th17 cell-mediated diseases.