bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gamma-delta TCR+ T-cells in systemic sclerosis (135.37)
Authors: Nwaneshiudu Adaobi , Jung Weon-ju , Tsygankov Alexander , Rayevskaya Marina , Oleszak Emilia , Myers Allen , Platsoucas Chris 
Published: January 2023

Abstract
T-cell involvement may be central to the pathogenesis of systemic sclerosis (SSc). Like αβ TCR+ T-cells, γδ TCR+ T-cell diversity during T-cell development results in a repertoire of different T-cells each with a unique TCR. Therefore the probability of finding identical TCR on defined T-cell populations is negligible, except in the context of an antigen-driven T-cell response. To determine whether γδ TCR+ T-cells are clonally expanded in skin biopsies and/or peripheral blood of patients with SSc (n=7), γ-chain (VγI & Vγ9) and δ-chain (Vδ1 & Vδ2) TCR transcripts were amplified by gene-specific PCR, followed by cloning and sequencing. We report the presence of substantial proportions of identical VγI-chain transcripts (14.3%-37.2%; p&lt;0.05), and Vγ9 transcripts (24%-83.3%; p&lt;0.05) in skin biopsies and/or PBMC of patients with SSc. Likewise, there were multiple identical Vδ1-chain transcripts (25%-50%; p&lt;0.05), and Vδ2-chain transcripts (18.1%-80%; p&lt;0.05) in the samples analyzed. Extensive clonal expansions of γ- and δ-chain TCR transcripts were identified in skin biopsies and peripheral blood of patients with SSc, demonstrating the presence of oligoclonal populations of γδ TCR+ T-cells in these patients. These γδ TCR+ T-cells may have undergone activation and clonal expansion in vivo in response to as yet unidentified antigens. Future studies to identify the antigens recognized by these clonally expanded γδ TCRs will facilitate better understanding of SSc pathogenesis.
When Toll-like receptor and T-cell receptor signals collide: A mechanism for enhanced CD8 T-cell effector function (136.11)
Authors: Geng Degui , Zheng Liqin , Asprodites Nicole , Velasco-Gonzalez Cruz , Davila Eduardo 
Published: January 2023

Abstract
Emerging reports reveal that activating toll-like receptor-2 (TLR)-MyD88 signals in CD8 T-lymphocytes enhances cytokine production and cytotoxicity. In the present study, we examined the physiological-significance and molecular mechanisms involved in this process. We found that TLR2 engagement on T-cell receptor transgenic CD8 OT-1 T-cells increased T-bet transcription factor levels and consequently augmented effector gene transcript and protein levels both in vivo and in vitro whereas, TLR2 agonist did not costimulate TLR2-/-OT-1 or MyD88-/-OT-1 T-cells. Elevated T-bet level in TLR2-MyD88-stimulated T-cells was a consequence of increased biosynthesis resulting from the enhanced activation of the mammalian target of rapamycin (mTOR) pathway. Inhibition of mTOR or blockade of phosphatidylinositol-3-kinase (PI3K)-Akt or PKC in T-cells abolished the costimulatory effects of the TLR2 agonist. In vivo, activating TLR2-MyD88 signals within OT-1 T-cells increased the levels of effector molecules and enhanced the clearance of Listeria monocytogenes-Ova. These results help define a signaling pathway linking the TLR-MyD88 and mTOR pathway in an Akt and PKC signaling-dependent manner, highlighting a critical role for TLR-MyD88 signaling in T-cell activation and cytotoxicity. These findings offer the opportunity for improving the efficacy of vaccines and T-cell-based tumor-immunotherapies by manipulating TLR-MyD88 signaling within CD8 T-cells.
NLRP3 inflammasome-dependent HMGB1 release induced by a bacterial pore-forming toxin (136.15)
Authors: Chu Jessica , Alber Sean , Watkins Simon , Núñez Gabriel , Salter Russell 
Published: January 2023

Abstract
The NLRP3 inflammasome is a caspase-1-containing complex involved in the maturation of pro-inflammatory cytokines IL-1β and IL-18. NLRP3, independent of its inflammasome functions, also plays a role in a cathepsin B-dependent, caspase-1-independent necrotic cell death process known as pyronecrosis. We have previously shown that the cholesterol-dependent, pore-forming toxin tetanolysin O (TLO) triggers IL-1β release from LPS-primed murine bone marrow-derived macrophages (BMDM) in a NLRP3 inflammasome- and cathepsin B-dependent manner. The work contained herein supports an additional role for TLO in the necrosis of LPS-primed BMDM. Both a low and a high TLO dose induce release of lactate dehydrogenase (LDH) and high mobility group box 1 (HMGB1) and this release is NLRP3-dependent for the low toxin dose. Low dose TLO-induced HMGB1 release is also dependent on the activities of caspase-1 and cathepsin B, suggesting a novel form of cell death that is distinct from caspase-1-independent pyronecrosis. We also observe via fixed cell microscopy that TLO causes HMGB1 to move from the nucleus to the cytoplasm in LPS-primed BMDM and that HMGB1 release is dependent on NLRP3 activity. To our knowledge, this is the first study to visualize HMGB1 localization in cells lacking NLRP3. These results provide information on the regulation of HMGB1 release and could eventually lead to new therapeutic approaches to target HMGB1, which contributes to many inflammatory diseases.
Progesterone minimizes immunoprotective effect of CpG ODN against infection by skewing immune responses toward Th17 (136.2)
Authors: Butts Cherie , Wang Vivian , Puig Montserrat , Verthelyi Daniela 
Published: January 2023

Abstract
Oligodeoxynucleotides encoding CpG motifs (CpG ODN), which activate the innate immune system and promote a strong Th1 response, are currently being tested in therapies for allergies and infectious diseases, including cutaneous leishmaniasis. Steroid hormones (such as progesterone) are associated with suppression of pro-inflammatory immune responses and a shift away from Th1 responses - critical for clearing intracellular parasites. Our assessment of progesterone effects on immune responses by mouse splenocytes in vitro and in vivo demonstrated a shift in the responses to CpG ODN characterized by limited upregulation of MHC Class II molecules by antigen presenting cells, lower IL-12 and IL-6, and increased IL-23 production. This was associated with increased IL-17 and lower IFN-γ secretion by CD4+ helper T cells. Similarly, progesterone treatment of human PBMCs stimulated with CpG ODN limited upregulation of CD83 and CD86 and decreased IFN-γ and IP-10 production. Assessment of whether the shift from Th1 responses by progesterone reduces the immunoprotective effects of CpG ODN in mice challenged with Leishmania major showed that orchiectomized mice receiving progesterone developed larger lesions than those receiving placebo and were not protected from disease when treated with CpG ODN. These data indicate that progesterone is able to skew immune responses by CpG ODN towards Th17 and contribute to disease susceptibility in women.
TLR4 augments HSV-2 induced NF-κB activity in human cervical epithelial cells (136.28)
Authors: Tang Xianying , Liu Hongya , Wu Xinxing , Li Hui 
Published: January 2023

Abstract
Herpes simplex virus type 2 (HSV-2) infects the genital epithelium and can be transmitted to the central nervous system, establishing lifelong infection. Toll-like receptors (TLRs) have been reported to initiate innate immune responses to microorganisms. It has been shown that TLR2 and TLR9 are involved in recognition of different HSV strains by dendritic cells (DCs). Our previous study has shown that HSV-2 infection leads to dramatic activation of the NF-κB signaling pathway and induction of IL-6 and IFN-beta. We report here that HSV-2 activates NF-κB reporter and TLR4/MD2 augments this activation. The NF-κB reporter construct was co-transfected into human cervical epithelial (HCE) cells together with either vectors or TLR4/MD2 expression plasmids. The transfected cells were then infected with HSV-2 at 3 MOI and luciferase activity was measured and normalized to Renilla luciferase activity. We observed a relatively low, but reproducible induction (approximately 1.5-fold) of reporter activity in HCE cells with HSV-2 infection compared to that in mock-infected cells. Importantly, an augmented induction of the NF-κB reporter was seen while cells were co-transfected with TLR4/MD2 in HSV-2 infected cells. Thus, TLR4 potentially plays a role in mediating its activation. Effect of shRNA against TLR4 on this induction is under active investigation. This work was supported by grants from the National Natural Science Foundation of China (No. 30500465, 30810103052)
Platelet-derived soluble TREM-Like Transcrip-1 (TLT-1) induces human and mouse Dendritic Cell activation through a TLR-4-dependent mechanism. (136.32)
Authors: de la Rosa Gonzalo , Tewary Poonam , Yang De , Gattis James , Lubkowski Jacek , Oppenheim Joost , McVicar Daniel , Washington Valance 
Published: January 2023

Abstract
Triggering Receptor Expressed on Myeloid Cells-Like Transcrip-1 (TLT-1) is a member of the multifunctional TREM family of receptors that also include TREM-1, 2, 3, and TLT-2. TLT-1 is expressed on megakaryocytes and platelets at low levels, but upon activation with thrombin, its membrane expression is up-regulated and shed, yielding a soluble form (sTLT-1). Here we describe for the first time the ability of human sTLT-1 to activate human monocytes and antigen-presenting cells. Treatment of myeloid Dendritic Cells (DCs) with sTLT-1 resulted in an increase of co-stimulatory molecules, induction of pro-inflammatory cytokines production, and their ability to prime lymphocyte proliferation. sTLT-1 failed to activate murine Bone Marrow-derived Dendritic Cells from TLR4-deficient mice, and blocking antibodies against TLR4 reduced sTLT-1-induced cytokine production by human monocytes and DCs, indicating that TLR4 is involved in sTLT-1 signaling. Therefore, human sTLT-1 has the ability to endow APCs with the capacity to initiate adaptive immune responses, and may therefore be a potential target of anti-inflammatory therapies.
Identification of the functional TLR4 TIR dimerization interface using a decoy peptide approach (136.37)
Authors: Toshchakov Vladimir , Szmacinski Henryk , Lakowicz Joseph , Vogel Stefanie 
Published: January 2023

Abstract
Agonist-induced oligomerization of TIR domains of TLRs and TLR adapters initiates intracellular signaling. Identification of TIR domain surface areas that mediate functional TIR-TIR interactions is key to the rational design of therapeutics that specifically target TLR signaling. We have designed a library of 11 cell-permeating decoy peptides each of which represents a non-fragmented patch of the TLR4 TIR surface, such that the library entirely encompasses the TLR4 TIR surface. Each peptide was synthesized in tandem with a cell-permeating sequence derived from Antennapedia homeodomain and tested for the ability to inhibit early cytokine mRNA induction and MAPK activation elicited in peritoneal murine macrophages by LPS. Five peptides, 4R1, 4R3, 4BB, 4R9, and 4αE, potently inhibited all manifestations of TLR4 signaling examined. These 5 peptides and a control peptide (CP) were then examined for the ability to bind directly to TLR4 TIR by FRET using time-resolved fluorescence spectroscopy. Peptides were labeled with Bodipy-TMR-X (BTX); the C-terminus of TLR4 was fused to Cerulean fluorescent protein (Cer). BTX-labeled peptides 4R1, 4BB, and 4αE efficiently quenched fluorescence of TLR4-Cer expressed in HeLa cells, indicating efficient FRET. BTX-4R3 exhibits weak quenching. BTX-labeled CP and 4R9 did not change TLR4-Cer fluorescence lifetime. These data suggest that the area between BB loop of TLR4 and its fifth helical region mediate TLR4 TIR dimerization.
Structural studies of Toll like receptor signaling adaptors. (136.45)
Authors: Snyder Greg , Jiang Jiansheng , Chen Kang , Fresquez Theresa , Smith Patrick , Snyder Nathaniel , Luchetti Timothy , Cirl Christine , Miethke Thomas , Tjandra Nico , Xiao Tsan 
Published: January 2023

Abstract
Signaling downstream of the Toll like receptors (TLRs) involves Toll-IL-1R homology (TIR) domains as well as recruitment of critical signaling adaptors MyD88 and TIRAP/Mal. Studies in human patients, dominant negative mutants and knockout mice have shown that mutations in Arg196, the BB loop, DD loop, “Poc” site Ile179 are critical for MyD88 TIR domain signaling and appropriate responses to pathogen stimuli. We previously reported the structure of MyD88 TIR domain that showed a unique conformation for its BB loop, as well as a crystallographic lattice that reveals interactions between the BB-DD and BB-EE loops. We now report additional crystal forms which retain BB-DD and BB-EE interactions as well as extend the resolution to 1.4 Å. A yeast two-hybrid analysis of the domain interface residues observed from the crystal structure lattice shows that key residues including the human Arg196Cys mutation are critically important for homotypic TIR domain binding. Additionally, we report NMR solution studies showing binding between MyD88 and bacterial TIR domain protein TcpC, which has been demonstrated to negatively regulate MyD88-dependent TLR adaptor signaling. Finally, we report the X-ray structure of a second critical TIR adaptor protein, TIRAP/Mal. We observe key residues and loops important for TIRAP/Mal adaptor function. Structural insights from these studies may aid our understanding of the molecular mechanisms by which TLRs and TIR domain adaptors interact and signal.
T. cruzi interference with host cell membrane integrity triggers the release of Plasma Membrane-derived Vesicles: A mechanism for entry into mammalian cells (137.1)
Authors: Ansa-Addo Ephraim , Inal Jameel 
Published: January 2023

Abstract
Trypanosoma cruzi is a flagellated protozoan transmitted by various insects of the Reduviidae family and the causative agent of the debilitating Chagas disease with 50,000 deaths per annum. The lack of an effective treatment for the chronic form means the disease still remains an important health issue in Latin America. Disease transmissions from human-to-human can occur through contact with contaminated blood, during pregnancy or blood transfusion. Moreover, new means of transmission from contaminated food, and sharing of intravenous needles, means the disease now has the potential to be an international threat and cases are being seen in North America, Europe and Japan due to increasing human migration. Parasite entry into cells involves complex processes, not well characterised, and so the rationale of this study was to identify other possible host cell invasion strategies. Here, we show that T. cruzi triggers the release of PMVs from host cells. Parasites then take advantage of the membrane breach to gain entry into cells before lysosome-mediated membrane repair. Furthermore, we show, that T. cruzi triggers release of PMVs through integrins and lipid raft microdomains, which are all present on the plasma membrane. Inhibiting the activation of these receptors by the parasite stops the release of PMVs and this inhibits T. cruzi entry into cells. This study adds to our knowledge on T. cruzi infection strategies and possible pathways that could be therapeutically targeted.
Regulatory T cell suppressive potency dictates the balance between bacterial proliferation and clearance during persistent Salmonella infection (137.11)
Authors: Johanns Tanner , Ertelt James , Rowe Jared , Lai Joseph , Way Sing Sing 
Published: January 2023

Abstract
The pathogenesis of persistent infection is dictated by the balance between opposing immune activation and suppression signals. Although regulatory T cells (Tregs) have been widely implicated to control host defense against infection, their role in dictating the natural progression of persistent infection remains incompletely defined. Herein, a sharp dichotomy in infection tempo between early and late time points during persistent Salmonella infection is demonstrated. Early after infection, blunted effector T cell activation and increasing bacterial burden coincide with enhanced Treg suppressive potency. Reciprocally, at later time points, robust effector T cell activation and bacterial clearance occur in parallel with diminished Treg suppression. By enumerating the relative impact of Treg ablation on infection outcome at both early and late time points of persistent infection, the role of Treg suppressive potency in dictating the natural progression of infection was verified. Thus, dynamic control of Treg suppressive potency dictates the tempo of persistent bacterial infection.
Immune Molecular Plasticity Links Viral Virulence to Protective T cell Vaccines (137.2)
Authors: Salek-Ardakani Shahram , Flynn Rachel , Arens Ramon , Yagita Hideo , Smith Geoffrey , Borst Jannie , Schoenberger Stephen , Croft Michael 
Published: January 2023

Abstract
Attenuated non-replicating or weakly replicating viruses are being used as vaccines but they generally elicit poor T cell immunity and might not afford optimal protection. We show that the virulence of a virus leads to altered levels of T cell memory because of the differential use of stimulatory receptors. Persistently replicating virus results in selective engagement of the TNFR family molecules OX40 (CD134) and CD27. These molecules drive enhanced CD8 T cell memory, and determine the protective capacity of a virus when used as a vaccine. Therefore the length of exposure to viral antigen results in the immune system engaging novel protein interactions, which are otherwise inactive. Defining this link between virulence and immunogenicity will aid the design of safe but still effective T cell vaccines.
IFN-γ expression by regulatory T cells in the CNS of mice persistently infected with neurotropic coronavirus (137.27)
Authors: Zhao Jingxian , Perlman Stanley 
Published: January 2023

Abstract
Mice infected with mouse hepatitis virus, strain JHM develop a chronic infection in the CNS characterized by low levels of viral antigen persistence and retention of virus-specific CD4 and CD8 T cells at the site of infection. We have previously demonstrated that T cell maintenance in the infected CNS is a dynamic process, requiring replenishment from peripheral antigen- experienced and naïve T cell pools. Since mice continued to show clinical improvement, these results raised the possibility that Tregs contributed to a quiescent state in the CNS. Here we show a preferential influx of Tregs to the CNS at very early stage of the infection. They are not converted from Foxp3- cells. Intriguingly, not only IL-10 but also IFN-γ producing Tregs are found in the CNS as early as d 5 p.i. While there are much less (&lt;1%) Tregs making IL-10 during chronic infection, a proportion (&gt;15%) of them continue to express IFN-γ. IFN-γ expression is correlated with T-bet upregulation in Tregs. IFN-γ producing Tregs are induced locally in the CNS from both virus-specific and nonspecific Treg pools. While the frequencies of total Tregs decrease dramatically by d 7 p.i. and remain constant thereafter, two thirds of Tregs lose their Foxp3 expression between d 7 and d 28 p.i. in adoptive transfer experiments. We propose that Tregs acquire effector cell phenotype during type 1 inflammation and the maintenance of Tregs in the persistently infected CNS is also dynamic, requiring recruitment of new Tregs.
Downregulation of TACI by Neisseria meningitidis type C polysaccharide vaccine is responsible for its weak immunogenicity (137.4)
Authors: Akkoyunlu Mustafa , Katsenelson Nora , Blake Milan , Kanswal Sunita 
Published: January 2023

Abstract
Antibodies against the capsular polysaccharide (CPS) antigen of Neisseria meningitidis are bactericidal against meningococcus. However CPSs are poorly immunogenic T cell independent type II antigens. The B cell molecule TACI is shown to be essential for the development of antibody response against CPS antigens. TACI is a receptor for the TNF family cytokines BAFF and APRIL. In this study, we have determined that the CPS of N. meningitidis-C (MCPS) inhibits BAFF or APRIL induced plasma cell development and Ig secretion from mouse B cells. Correlating with this, TACI was strongly downregulated in MCPS exposed B cells. BAFF activates both the classical and alternative NF-kB pathway in B cells. Investigation of BAFF mediated signaling demonstrated that MCPS inhibits both the signaling pathways. Previously, we had shown that CpG strongly upregulates TACI expression. We therefore tested whether CpG would block the inhibitory effect of MCPS. The results showed that CpG partially reversed TACI suppression induced by MCPS. Supporting these in vitro results, CpG was not able to augment antibody response against MCPS when a CpG containing MCPS vaccine was injected into mice. Taken together our data demonstrates that CPS mediated downregulation of TACI on B-cell surface could be a mechanism by which meningococcal bacteria evade host immune response. Also, inhibition of B cells through suppression of TACI may explain the poor immunogenicity of CPS based vaccines.
Regulation of virus-specific acute and memory CD8+ T cell response by Galectin-9/TIM-3 interaction (137.5)
Authors: Sehrawat Sharvan , Hirashima Mitsuomi , Rouse Barry 
Published: January 2023

Abstract
We demonstrate that galectin-9 (Gal-9) acts to constrain CD8+ T cell immunity to Herpes Simplex Virus (HSV) infection. In support of this, we show that animals unable to produce Gal-9, because of gene knockout, develop acute and memory responses to HSV that are of greater magnitude and better quality than those that occur in normal infected animals. Interestingly, infusion of normal infected mice with α-lactose, the sugar that binds to the carbohydrate-binding domain of Gal-9 limiting its engagement of T cell immunoglobulin and mucin (TIM-3) receptors, also caused a more elevated and higher quality CD8+ T cell response to HSV. Such sugar treated infected mice also had expanded populations of effector as well as memory CD8+ T cells. The increased effector T cell responses led to significantly more efficient virus control. The mechanisms responsible for the outcome of the Gal-9/TIM-3 interaction in normal infected mice involved apoptosis of TIM-3+ Teffectors as well as the promotion of Foxp3+ regulatory T cell activity. Our results indicate that manipulating galectin signals, as can be achieved using appropriate sugars, may represent a convenient and inexpensive approach to enhance primary and memory responses.
IL-28(IFN-lambda) inhibits Th2-mediated allergic airway inflammation through the modulation of dendritic cell function (138.11)
Authors: Übel Caroline , Kolsida Ourania , Hausding Michael , Andreakos Evangelos , Finotto Susetta 
Published: January 2023

Abstract
IL-28(IFN-Lambda) is a newly discovered cytokine that is profoundly down-regulated in allergic asthma. Here, we reveal a novel role of IL-28 in suppressing Th2 cell differentiation and Th2-mediated pathology. Inhibition of endogenous IL-28 function in IL-28Ralpha-/- mice exacerbated allergic airway disease by augmenting Th2 responses and IgE levels, and down-regulating Th1 and regulatory T cell responses. Moreover, treatment of wild-type mice with recombinant or adenovirally-expressed IL-28 ameliorated allergic airway disease, suppressed Th2 responses and induced IFN-gamma and CD4+CD25+FoxP3+ regulatory T cells. Central to IL-28 immunoregulatory activity was its capacity to modulate CD11c+ conventional DC function to down-regulate OX40L, up-regulate T-bet and IL-12, and promote Th1 cell differentiation. Consistently, IL-28-mediated protection was absent in IFN-gamma-/- mice and was adoptively transferred by IL-28-treated CD11c+ cells. These data demonstrate a critical role of IL-28 in controlling T cell responses in vivo through the modulation of conventional DC function in models of allergic asthma.