bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective Activation of Antigen-Specific T Cells by Anti-CD3 Constraining Nano-particles (58.15)
Authors: Lo Ying-Chun , Edidin Michael , Powell Jonathan 
Published: January 2023

Abstract
Upon antigen (Ag) recognition, TCRs form nanoscale clusters on the T cell surface. We hypothesized that the spatial differences of surface TCR between naïve and previously activated cells might be exploited by using anti-CD3 coated quantum dots (Qdots) to selectively activate Ag-specific cells. Rag-/- Pigeon Cytochrome c (PCC) specific CD4+ T cells were activated with APC +/- PCC with or without anti-CD3 Qdots. Anti-CD3 Qdots markedly enhanced proliferation of T cells incubated with low dose PCC but did not drive proliferation of T cells incubated with APC alone, though such cells proliferated to soluble anti-CD3. Additionally, anti-CD3 Qdots increased cytokine production of such cells in TH1 and TH2 cultures. We also explored the effect of anti-CD3 Qdots on heterogeneous cultures containing Rag+/+ hemagglutinin peptide (HA) specific 6.5+ CD4+ T cells and bystander 6.5- CD4+ T cells. Soluble anti-CD3 resulted in proliferation of both 6.5+ and 6.5- T cells. Cultures including low dose HA induced only 6.5+ T cells to proliferate, and addition of anti-CD3 Qdots further selectively enhanced proliferation of 6.5+ T cells but not 6.5- T cells in the same culture. This effect was again seen using CD8+ TCR transgenic T cells specific for class I HA. In vivo, anti-CD3 Qdots also increased the recovery of 6.5+ cells in a 6.5 adoptive transfer and HA vaccination model. Thus, constraining anti-CD3 on a nanoparticle confers an Ag-specific “nano boost” to T cell proliferation and function.
Regulating immune responses to biologics: Epitope prediction and applications (58.23)
Authors: Cousens Leslie , Moise Lenny , Ardito Matthew , McClaine Elizabeth , Terry Frances , Martin William , De Groot Anne 
Published: January 2023

Abstract
Immune responses directed against protein therapeutics can directly impact drug safety and efficacy. The ability to predict and reduce immunogenicity of a potential protein therapeutic presents tremendous benefits at every stage of drug development. While many factors contribute to protein immunogenicity, T cell-dependent responses play a critical role. We report two approaches to mitigate therapeutic protein immunogenicity, one involving epitope modification and the other inducing antigen-specific tolerance induction. Rational epitope modification applied to either Factor VIII or botulinum toxin demonstrates reduced immunogenicity when following a systematic process of in silico epitope mapping, in vitro and in vivo validation of computational predictions, iterative in silico modification of immunogenic epitopes and experimental validation of carefully selected modified sequences. Tolerance induction involves co-delivery, chemical or recombinant linkage of regulatory T cell epitopes (Tregitopes) to therapeutic proteins. We have demonstrated that Tregitope incorporation leads to lower immune responses against target epitopes identified in insulin, Factor VIII and botulinum toxin. The ability to analyze, predict, and modify the immunogenicity of a protein expands the available strategies for mitigating therapeutic protein immunogenicity, enables quality by design for drugs in development and improvement of licensed biologics to create biobetters.
Antigen-induced release and retroviral subversion of TCR-enriched microvesicles at the CD4+ T cell immunological synapse (58.5)
Authors: Choudhuri Kaushik , Llodra Jaime , Kam Lance , Stokes David , Dustin Micheal 
Published: January 2023

Abstract
The immunological synapse (IS) is a specialized junction that forms between T cells and antigen presenting cells, which is critical for effective T cell antigen recognition and effector functions. Its spatiotemporal evolution results in laterally segregated supramolecular domains composed of a peripheral adhesive ring of the β2 integrin LFA-1 and its ligand ICAM-1, and centrally accumulated T cell receptors (TCR). The molecular and cell biological basis for supramolecular domain organization at the IS remains unclear. Here we show, using novel correlative optical-electron microscopy methods in conjunction with electron tomography, that centrally accumulated TCR is located on the surface of microvesicles that are shed at the IS center. The ESCRT I member TSG101 sorts TCR into microvesicles. TCR-enriched microvesicles (TEMs) are transferred from T cell to B cell during cognate antigen recognition, and B cells initiate intracellular signals in response to TEMs, suggesting their involvement in intercellular communication between immune cells. Expression of the HIV GAG structural polyprotein in human CD4+ T cells, displaces TCR from microvesicles at the IS, resulting in the release of GAG-containing virus-like particles. These findings provide an ultrastructural basis for supramolecular domain organization at the IS, and identify an ESCRT-dependent mechanism for production of stimulatory TEMs, which may be co-opted during infection for the release of enveloped viruses.
A novel monoclonal antibody against the human IL-17AF heterodimer for flow cytometry (59.11)
Authors: Schifano Matthew , Araji Soha , Li Shourong , Ruiz Natalie , Schrantz Nicolas , Huang Qiulong , Just Peggy 
Published: January 2023

Abstract
The IL-17 family members, IL-17A and IL-17F, are signature Th17 cytokines. Although they were both originally found to be produced as disulfide-linked homodimers, recent studies have confirmed the production of IL-17AF heterodimers in in vitro-differentiated and polarized Th17 cells. While ELISA-based assays have become available for the study of these heterodimers, flow antibodies have been generated only to the monomeric subunits, making discrimination between the homo- and heterodimer complexes difficult. Here, for the first time, we use a novel monoclonal antibody to identify producers of the IL-17AF heterodimer by flow cytometry. Under our polarization conditions, the majority of human lymphocytes that stain for both IL-17A and IL-17F also stain for the IL-17AF heterodimer. These results suggest that this population produces mostly IL-17AF heterodimers and not the IL-17A and IL-17F homodimers alone. This novel reagent will help expand our knowledge of the IL-17/Th17 axis and contribute to the elucidation of its role in the immune response.
Adaptive immune response in pulmonary hypertension (59.13)
Authors: Grunig Gabriele , Chen Wen-Chi , Hoffman Carol , Gordon Terry , Park Sung-Hyun 
Published: January 2023

Abstract
Immune responses have long been associated with pulmonary arterial hypertension. Previous studies in our lab have shown that a prolonged T helper 2 (Th2) response to inhaled antigen induces severe pulmonary arterial remodeling and that this is exacerbated by urban particulate matter (PM) from air pollution. The present study was designed to identify the role of the adaptive immune response (B cells, IL-13, IL-17) in pulmonary hypertension induced by antigen and urban PM. The respirable fraction of airborne PM (PM2.5) was collected in New York City. Th2 primed mice were challenged with soluble antigen (Ovalbumin) combined with urban PM2.5 intranasally. We determined pulmonary arterial remodeling by histology, right heart hypertrophy by ventricular weight measurements and right ventricular systolic pressures recorded in anaesthetized, spontaneously breathing mice. In contrast to wild type, B cell KO mice had no significantly increased right heart weights, or right heart systolic pressures in response to intranasal antigen and urban PM2.5. Reconstitution with anti-antigen antibody restored the development of pulmonary hypertension in these mice. Combined blockade of IL-13 and IL-17 significantly ameliorated pulmonary hypertension induced in wild type mice exposed to antigen and urban PM2.5. Our studies indicate that antigen-specific antibody, IL-13 and IL-17 are necessary for the development of pulmonary hypertension induced by the exposure to antigen and urban PM2.5.
Dysregulated production of IL-17 by γδ T cells in the absence of interleukin-15 receptor α (59.2)
Authors: Colpitts Sara , Pham Quynh-Mai , Lefrançois Leo 
Published: January 2023

Abstract
Interleukin (IL)-15 and the IL-15 receptor α-chain (IL-15Rα) are required for the homeostasis of certain subsets of γδ T cells. We sought to determine if IL-15 signaling was also required for the generation and maintenance of a unique subset of IL-17-producing (IL-17+) γδ T cells. Surprisingly, we found a significant increase in the percentage and total number of IL-17+ γδ T cells in IL-15Rα KO (RKO) mice, most notably in the spleen, mesenteric lymph node, liver, and thymus. By generating mixed chimeras from WT and RKO neonatal thymocytes, we determined that the effect was not cell-intrinsic since WT- and RKO-derived γδ T cells exhibited equivalent IL-17 production. Considering the dissemination of IL-17+ γδ T cells to peripheral tissues, we hypothesized that their migration could be altered in RKO mice. Using parabiosis, we found that IL-17+ γδ T cells did not equally distribute between joined WT mice, suggesting limited recirculation, but also observed unexpected recirculation of IL-17+ γδ T cells into the thymus. When comparing WT:WT versus RKO:RKO parabionts, there was a significant increase in the percentage of IL-17+ cells in the donor γδ T cell population of RKO pairs, suggesting increased recirculation in the IL-15Rα-deficient environment. These findings support the presence of a cell-extrinsic effect of IL-15Rα signaling in regulating the IL-17+ γδ T cell subset. Further studies will continue to dissect the mechanism(s) by which this regulation occurs.
IL-23 promotes autoimmune Th17 memory formation and function (59.6)
Authors: McGeachy Mandy , Haines Christopher , Chen Yi , Blumenschein Wendy , McClanahan Terri , Cua Daniel 
Published: January 2023

Abstract
IL-23 is essential for the differentiation of pathogenic effector Th17 cells, but little is known about its requirement in memory Th17 responses. To investigate autoimmune Th17 memory, we developed a variation of the experimental autoimmune encephalomyelitis model, in which CD4+ T cells from MOG(35-55)-immunized donors were transferred into naïve recipients and rested before re-challenge. Following secondary recall, memory Th17 cells rapidly expanded in lymph nodes before trafficking to the central nervous system in high numbers, resulting in earlier onset and increased severity of clinical signs. Th17 memory cells were generated from IL-17+ and RORγt+ precursors, and stability of the Th17 phenotype was dependent on time. IL-23 was required during the primary response for generation of Th17 memory cells During the recall response, IL-17 production was not directly impacted by neutralizing IL-23R at secondary challenge, but the generation of effectors that co- expressed T-bet was strongly impaired. In addition, IL-23R blockade resulted in decreased proliferation and reduced total numbers of Th17 memory cells in the secondary response.
B7x deficiency exacerbates renal injury in antibody mediated nephritis (60.7)
Authors: Pawar Rahul , Goilav Beatrice , Xia Yumin , Ghosh Kaya , Herlitz Leal , Zang Xingxing , Putterman Chaim 
Published: January 2023

Abstract
B7x (B7-H4, B7S1) is an important member of the B7/CD28 superfamily of T cell costimulatory proteins. B7x is a negative regulator of CD4+ and CD8+ T cell activation and proliferation, and is expressed in both hematopoietic and non-hematopoietic tissues. We hypothesized that B7x is instrumental in the pathogenesis of antibody mediated nephritis. To examine this question we induced nephritis in B7x-deficient (B7x-/-) (n=10) and WT B6 mice (n=10) by passive transfer (i.v.) of nephritogenic antibodies. Following induction of nephritis, we found a marked increase in the levels of serum IgG (p=0.023), IgG2b (p=0.055), and IgG1 (p=0.064) in B7x-/- mice compared to WT mice. Moreover, renal damage was more severe in B7x deficient mice. Serum creatinine and BUN were elevated in the B7x-/- group compared to the WT mice. Furthermore, B7x-/- mice demonstrated worse kidney histopathology, with an increase in infiltrating PMN cells in glomeruli (p&lt;0.0001) and interstitium (p=0.004), crescent formation, and tubular atrophy/dilatation. Immunohistochemical studies revealed increased glomerular infiltration of CD3+ T cells (p=0.034) and CD68+ macrophages (p=0.003) in B7x-/- mice kidneys. At the mRNA level, IL-23 was significantly upregulated in kidneys of B7x-/- mice. Thus, B7x plays a protective role in the pathogenesis of antibody mediated nephritis. The relative contributions of systemic versus local immune effects of B7x in nephrotoxic nephritis are currently being investigated.
Low frequency of iNKT cells in Type 1 Diabetes Patients and their first degree relatives: A Mexican Cohort (60.9)
Authors: Beristain-Covarrubias Nonantzin , Canché-Pool Elsy , Vaal-Aguilar Mayra , Gómez-Díaz Rita , Ortiz-Navarrete Vianney 
Published: January 2023

Abstract
Type 1 Diabetes (T1D) is a chronic, autoimmune disease, characterized by specific destruction of the insulin producing pancreatic β cells. This destruction is mediated by auto-reactive T cells. Lymphocytes NKT play an important role in type 1 diabetes (T1D) pathogenesis. Data from the NOD mouse shows a numerically and functionally deficient NKT cell, and those produce subnormal levels of IL-4 and IFNγ when stimulated. Similar defects have been suggested in humans, although they are not conclusive, some studies predict a role for NKT cells in T1D development. Class I Restricted T Cell Associated Molecule (CRTAM) is expressed at the cell surface of activated human invariant NKT cells (iNKT), CD8 and CD4 T cells. Recently we analyzed a cohort of 42 T1D patients, 103 relatives (mother, father and sibling), and 40 healthy controls. We found a significant low percentage and absolute number for iNKT in T1D patients, and identified two cell populations among the iNKT cells (iNKThi and iNKTlo). High levels of Va24/Vb11 (TCR) were observed for the iNKThi whereas the iNKTlo expressed low levels of TCR and it was CRTAM positive.
Expression pattern of agonist antigen influences timing of thymic selection (63.5)
Authors: Ju Ji Min , Jeon Ji Yeong 
Published: January 2023

Abstract
MHC complexes with peptides from minor histocompatibility (H) antigens which are naturally occurring polymorphic proteins are recognized by T cells. The mismatches at the Minor H loci induce allo-reactive T cell activation, leading to graft-rejection, graft-versus-host disease, or graft-versus-leukemia under MHC-matched transplantation circumstances. T cell response specific for H60 has been characterized as a dominant. In order to investigate the effect of antigenic expression pattern on the outcome of bone marrow transplantation, we generated a TCR transgenic mouse (named J15), of which specificity is H60 peptide in complexes with H2-Kb, with TCR α and β genes were originated a H60-specific CTL clone. The thymocytes in the J15 mice mostly developed to CD8 T lineage and showed proliferation in response to H60-stimulation. The thymocytes bearing J15 TCR were deleted in the mice where H60 are expressed in hematopoietic cell-restricted pattern and ubiquitously, that is in the F1 mice after crossing of J15 to H60 congenic (J15TgH60C/-) or to H60 transgenic mouse (J15TgAct-H60Tg), respectively. But the deletion timing was different during the double negative stages between the two F1 mice. The different deletion timing was observed when the bone marrow chimeras were generated with H60 congenic mice and with Act-H60Tg mice as hosts into which bone marrow from the J15 were transferred. These results demonstrate that antigen expression pattern influences the thymic selection timing.
ShcA and c-Abl provide a new signaling axis regulating beta-selection (63.8)
Authors: Trampont Paul , Zhang Li , Giles Amber , Walk Scott , Pendergast Ann Marie , Ravichandran Kodi 
Published: January 2023

Abstract
Progression of immature CD4-CD8- thymocytes through β selection checkpoint is determined by signals from the pre-T cell receptor (pre-TCR) along with signals from Notch. Knockout of the adapter protein ShcA, or transgenic expression of a phosphorylation-defective mutant of ShcA (ShcFFF) leads to a severe block at β selection. Our studies to mechanistically understand the ShcA function showed that ShcA acts upstream of ERK, and the transcription factors Egr-1 and Egr-3 during β selection; however, phospho-ShcA also appeared to be linked to other signaling pathways. We performed a yeast three-hybrid screen, using as bait ShcA that was phosphorylated by Lck. This screen identified binding of c-Abl (via its SH2 domain) to phosphorylated ShcA. During pre TCR dependent signaling, phosphorylation of ShcA was required for optimal c-Abl phosphorylation. Using mice deficient either in c-Abl and/or its homologue Arg, we show that ShcA and c-Abl regulate DN thymocyte proliferation, and the proper localization of DN thymocytes near the thymic cortex. Ectopic expression of a constitutive active c-Abl allowed thymocytes to resume proliferation, differentiation, and CXCR4 dependent migration to SDF-1α. Collectively, these data reveal a previously unappreciated ShcA::c-Abl signaling axis that appears to critically influence thymic β selection.
The role of CD4+CD40+ cells in EAE mice. (65.1)
Authors: Carter Jessica , Wagner David 
Published: January 2023

Abstract
Auto-aggressive T cells are responsible for the onset and perpetuation of autoimmune diseases, including Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). A subset of CD4 T cells, CD4+CD40+ cells, have an expansive role in the Non-Obese Diabetic (NOD) mouse model of T1D. Not only do CD4+CD40+ cells increase in number with the onset of disease, but they are necessary and sufficient in transferring T1D from NOD to NOD.scid mice. Because CD4+CD40+ cells have an imperative role in the development of disease in T1D, we considered that these cells might also be involved in Experimental Autoimmune Encephalomyelitis (EAE), a neurological disease which mimics human MS. When given myelin oligodendrocyte glycoprotein (MOG) and pertussis toxin (PT), C57Bl/6 mice develop neurological symptoms and impaired motor functions similar to those in human MS patients. Data shows an increase, not only in CD4 T cells, but also in CD4+CD40+ cells in mice receiving induction of EAE. This does not occur in their control counterparts. Further, purified splenic CD4+CD40+ cells from asymptomatic disease induced C57Bl/6 mice rapidly transfer EAE to C57Bl/6.scid recipients with only 1.2x106 cells, demonstrating that CD4+CD40+ cells alone can induce EAE. Also, we show cerebral infiltrates of immune cells in localized regions of the brain of the CD4+CD40+ recipient mice, suggesting that these lesions are similar to the lesions found in human MS patients.
Induced-tolerogenic Dendritic Cells promote tolerance and de novo differentiation of regulatory T cells (65.6)
Authors: Maldonado Roberto , Perdomo L. Carolina , Vascotto Fulvia , Bauquet Aurelie , Sharpe Arlene , Kuchroo Vijay , von Andrian Ulrich 
Published: January 2023

Abstract
Tolerance towards specific antigens is achieved by elimination of reactive T cells and/or their differentiation into regulatory T cells (Tregs). We screened several cell culture conditions known to confer potent tolerogenic capacity on Dendritic Cells (DC) in an attempt to obtain antigen-presenting cells that eliminate naïve CD4+ T cells (Tn) or induce Foxp3 expression, the master regulator of Treg differentiation and function. We identified Rapamycin and TGFβ as key factors that imprint DCs with strong tolerogenic function. TCR stimulation of Tn by these induced-tolerogenic DC (itDC) results in the selective reduction of antigen specific cells and the upregulation of Foxp3 expression in the remaining cells. The resulting adaptive regulatory T cells (aTregs) express high levels of CD25, GITR, CD152, CD62L and suppress T cell responses in vitro. Interestingly, aTreg differentiation induced by itDC was cell contact-dependent and occurred in absence of IL-10, TGFβ, IDO1 and FasL. In vivo injection of itDCs at the first clinical signs of MOG-induced Experimental Autoimmune Encephalomyelitis (EAE, Day 12) completely blocks the progress of the disease. Finally, monocyte-derived human itDC also induced sustained Foxp3 expression in human T cells that display suppressive function. These results suggest that itDCs may be a valuable tool to induce antigen-specific tolerance in vivo and represent a potential novel therapy for autoimmune disorders.
Neutrophils Suppresses Protective Immunity and Mediates Immunopathology in Mice during Fatal Bacterial Infection-Induced Toxic Shock (67.1)
Authors: Ismail Nahed , Ismaeel Nourhan , Yang Qin , Al-Hendy Omar , Ghose Purnima 
Published: January 2023

Abstract
Ehrlichia chaffeensis is an obligate intracellular bacteria that causes systemic infection and fatal toxic shock-like syndrome in immunocompetent patients. The balance between protective immunity mediated by CD4+Th1 cells, and immunopathology, which is mediated by NK and CD8+T cells, determines the outcome of Ehrlichia infection in mice. Early recruitment of neutrophils to the sites of infection is critical for the control of bacterial infection. However, the contribution of neutrophils to protective immunity or immunopathology during Ehrlichia infection remains undefined. Compared to innocuous ehrlichial infection, lethal high-dose Ehrlichia infection of wild type mice is associated with a substantial expansion of activated neutrophils at the main sites of infection and a substantial TLR2 signaling. Surprisingly, depletion of neutrophils from lethally-infected mice enhanced bacterial elimination, decreased immune -mediated pathology, and prolonged survival. Furthermore, neutrophil depletion in infected mice resulted in amelioration of pathogenic responses as evidenced by abrogation of cytokine and chemokine storm and decreased frequency of pathogenic TNF-alpha- producing CD8+T cells compared to lethally infected isotype controls. These results revealed an unexpected role of neutrophils in suppression of protective immunity and mediating immunopathology during infection with intracellular bacteria.
Serum amyloid A and apolipoprotein E alter the host innate immune response elicited by malarial hemozoin (68.14)
Authors: Kassa Fikregabrail , Shio Marina , Olivier Martin 
Published: January 2023

Abstract
Malaria is one of the most important infectious diseases worldwide and still remains to be the major cause of death in tropical countries. The intraerythrocytic stage of the malaria parasite results in the production and release of hemozoin (HZ). Recently we have identified that HZ specifically interacts with serum proteins such as serum amyloid A (SAA) and apolipoprotein E (ApoE). In our current work, we were interested to determine the impact of these proteins on the macrophage’s innate immune response triggered by HZ. Since HZ induces IL-1β production via the NLRP3 inflammasome, we looked at the production of IL-1β using PMA-differentiated THP-1 cells. IL-1β, along with TNF-α, is considered to be the major contributor for malaria pathology. Our results show that SAA bound to HZ induces the production of IL-1β in a dose dependent manner. Furthermore, HZ-SAA and hemozoin-ApoE complexes phosphorylate the MAPKs specifically ERK1/2 and JNK. This is in agreement with the observation that SAA activates downstream signaling pathways via LYN resulting in the activation of ERK1/2 and JNK. Apart from IL-1β production, HZ bound serum proteins also modulate ROS production and phagocytosis in THP-1 cells. Overall, our results show that serum inflammatory proteins adhering on HZ modify its capacity to stimulate phagocytosis, IL-1β and ROS productions by THP-1 cells upon stimulation, suggesting that such cooperation could greatly influence the development of malaria-related pathologies.