bluuebunny/crossref_metadata_2025_split huggingface dataset:
Omicron Breakthrough Infection Elicits Superior Humoral and Mucosal Immunity to SARS-CoV-2 Variants than Booster Doses
Authors: Nantel Sabryna , Sheikh-Mohamed Salma , Chao Gary , Hu Queenie , Kurtesi Alexandra , Wood Heidi , Colwill Karen , Seifried Laurie , Bourdin Benoîte , Brockman Mark , Piccirillo Ciriaco , Quach Caroline , Gingras Anne-Claude , Gommerman Jennifer , Decaluwe Hélène 
Published: August 2023

Abstract
In light of ongoing booster vaccination campaigns, one recurring question is whether individuals infected with SARS-CoV-2 should still receive a booster dose if they were infected after completing their primary series. We aimed to assess the intensity of functional humoral and cellular immune responses induced by breakthrough infections during the B.1.1.529 wave in Canada compared to individuals who received three doses of vaccine. Because hybrid immunity has been shown to induce particularly potent immunity, we hypothesized that breakthrough infections could induce superior immune response to variants than booster doses.
To address this important public health question, we analyzed samples from two cohorts of individuals naïve to SARS-CoV-2 or who were primary infected before vaccination. We compared responses 45 days after a third vaccine dose or an Omicron breakthrough infection. Our results show that mild breakthrough infection induces cell-mediated immune response to variants comparable to a vaccine booster dose. In contrast, breakthrough subjects had higher salivary IgG and IgA levels against the Omicron Spike and enhanced reactivity to the ancestral Spike for the IgA isotype, which also reacted with SARS-CoV-1. Serum neutralizing antibody levels against the ancestral strain and the variants were also higher after breakthrough infection, especially in individuals naïve to the infection prior to vaccination. Altogether our results demonstrate that an Omicron breakthrough infection can substitute a booster dose of vaccine, while also supporting the need for mucosal vaccine boosts to potentially replicate the improvement on mucosal and humoral immunity without the risks associated to being infected with SARS-CoV-2.
Research supported by grants from the Canadian Institutes of Health Research, Public Health Agency of Canada and the Ontario COVID-19 Rapid Research Fund through Ontario Together.
Radiation causes long term changes in virus-specific and virtual memory CD4 T cells
Authors: Kannan Shravan Kumar , Heidarian Mohammad , Swanson Whitney , Griffith Thomas S , Harty John T , Badovinac Vladimir P 
Published: August 2023

Abstract
Threat of nuclear attack and accidents at nuclear power plants increase our risk of radiation exposure. Radiation effects on immune homeostasis are well-studied, but their effect on memory CD4 T cells is poorly defined. To explore that, we adoptively transferred naïve Thy1.1 TCR-Tg SMARTA CD4 T cells specific for LCMV-derived gp61 epitope into naïve Thy1.2 C57BL/6 mice before LCMV-Armstrong infection. At memory time point, infected recipient mice were subjected to 0Gy (non-radiated, control group) or 5Gy of total body radiation. We found that naïve CD4 T cells suffered significant numerical loss post radiation, but they numerically recovered in few weeks through increased proliferative expansion. However, radiated SMARTA and endogenous GP61-specific memory CD4 T cells sustained a prolonged loss in number that fail to recover even after 3 months. Radiation also leads to transient impairment in the ability of memory CD4 T cells to produce cytokines (IFNγ, TNFα) in response to cognate antigen stimulation, or to proliferate upon adoptive transfer into new hosts in response to secondary LCMV infection. Interestingly, the endogenous ‘effector-like’ CD4 T cell numbers recovered faster than SMARTA memory T cells. We hypothesized that virtual memory T cells (CD4 Tvm) are contributing to the recovery of this effector like CD4 T cells in the radiation mediated lymphoreplete conditions. Tetramer enrichment of CD4 T cells specific to the gp66 and 2W1S epitope showed that radiation increases the representation of gp66 specific CD4 Tvm in naïve mice. Together, these data suggest that radiation poses long-lasting defects to virus specific memory CD4 T cell responses, and it facilitates CD4 Tvm proliferation to overcome the lymphopenia.
Disruption of IL-33-mediated costimulation to CD4+ T cells leads to peripheral Treg generation and resolution of T cell-mediated pathology
Authors: Dwyer Gaelen K , Mathews Lisa , Lee Amanda H , Saba Johnny Bou , Beeravolu Harshita , Villegas Vazquez Jose A , Poholek Amanda , Blazar Bruce R , Luther Sanjiv A , Shlomchik Warren D , Turnquist Heth Roderick 
Published: August 2023

Abstract
Stromal signals are becoming appreciated as critical coordinators of immunity. We recently demonstrated that fibroblastic reticular cell (FRC)-derived IL-33 directly stimulates CD4+ T cells during priming to promote IL-12-independent Type 1 T helper cell (Th1) differentiation and expansion. Utilizing TCR transgenic (Tg) T cells lacking the IL-33 receptor, ST2, we established that IL-33 is a costimulatory molecule augmenting TCR signaling to low affinity or concentration antigens. Blockade of costimulatory molecules can lead to peripheral regulatory T cell (pTreg) induction and our RNAseq analysis suggested that the absence of early IL-33 stimulation increased CD4+ T cell expression of IL-10 and Foxp3. Thus, we hypothesized that disruption of the ST2/IL-33 pathway in CD4+ T cells would mediate pTreg generation and the resolution of T cell-mediated pathology. To test this hypothesis, we compared Tg B6 mice allowing inducible ST2 deletion (R26-CreERT2xSt2fl/fl (ST2FL) to wildtype (WT) R26-CreERT2 (ST2WT) as T cell donors in a CD4-driven, lethal Graft-vs-Host Disease (GVHD) model. Irradiated BALB/c recipients received WT CD45.1+ bone marrow and either ST2WT or ST2FL. Recipient mice received tamoxifen (TAM) on days 10–14 post-transplant. Assessment of CD45.1−CD45.2+Kd−CD4+ T cells at day 21 revealed robust ST2 deletion associated with increased Foxp3+ expression in effector populations (CD4+CD44+CD69+CD62L−CCR7− and CD44+CD69−) in the lymphoid organs and tissues. TAM-treated recipients of ST2FL T cells had improved GVHD clinical scores and weight gain compared to ST2WT. Thus, IL-33 is a novel and potent stromal cell-derived costimulatory signal whose targeting may help resolve active CD4+ Th1 cell-mediated pathology.
Supported by grants from NIH R01AR073527, R01HL22489, and R56AI139327 (to HRT); and T32CA082084 and F30AI147437 (to GKD).
PAXBP1 SERVES AS A NOVEL REGULATOR OF T HELPER SPECIFICATION BY RESTRAINING THE TYPE 1 PROGRAM
Authors: Chisolm Danielle Alexandria , Morimoto Yuki , Philips Rachael Laura , Nagashima Hiroyuki , Meremikwu Ijeoma , Meylan Francoise , Yao Chen , Chaitankar Vijender , O’Shea John J , Kanno Yuka 
Published: August 2023

Abstract
To properly extinguish a diverse number of pathogens naïve T cells speciate into several T helper subsets in a highly regulated manner. In order to identify novel regulators of T helper specification we explored single cell RNA-seq datasets of T cells exposed to several different challenges. From this analysis, we found Paxbp1, a poorly described nuclear factor, was highly expressed in Th2 cells with its expression correlating well with Gata3. To understand the role Paxbp1 plays in T helper differentiation we generated a mouse model where Paxbp1 was deleted in T cells using a CD4cre model. Analysis from scRNA-seq reveal that Paxbp1 deficiency leads to a decrease in mature naïve T cells in both the thymus and periphery. Moreover, loss of Paxbp1 results in an aberrant expression of a Type I program, despite being exposed to a Type 2 environment in a reductionist approach; specifically, Paxbp1 deficiency results in the expression of what appears to be a terminal cytotoxic program. During in vivo challenges, T cells from Paxbp1 deficient animals recapitulated these results showing an increase in expression of the Type 1 program. Current work is aimed at determining the function of Paxbp1 by identifying binding partners through mass spectrometry. Additionally, we will use scATAC-seq to define transcription factors with differential activity in Paxbp1 deficient T cells. Altogether, our data suggests that Paxbp1 may be a previously unrecognized player in T helper specification and development that constrains inappropriate expression and accessibility of programs employed by alternative lymphocyte lineages.
CD9 identifies and regulates a highly functional and unique subset of T follicular helper (Tfh) cells necessary for the promotion of antibodies during infection
Authors: Weinstein Jason D , Antao Olivia , Sanchez Gina Marie , Petersen Kyleigh , Francis Rebecca , Mayer Daniel 
Published: August 2023

Abstract
T follicular helper (Tfh) cells comprise a subset of CD4+ T helper (Th) cells phenotypically and functionally distinct from Th1 and Th2 cell subsets. Tfh cells are located within B cell follicles and germinal centers (GC), where they secrete the cytokines IL-21 and interferon-γ (IFN-γ) which aid in B cell proliferation and differentiation. CD9, a tetraspanin, has been shown to accumulate on CD4 T cells at the immunological synapse, playing a role in co-stimulation and stabilization of the synapse via regulation of the integrins LFA-1 and VLA-4. CD9 has been shown to be expressed on activated CD4 T cells, but whether it remains upregulated specifically on Tfh cells is unknown. We identified a distinct population of CD9-expressing Tfh cells (CD9hi) following acute viral infections and examined their role in promoting GC responses. Following acute LCMV infection, CD9hi Tfh cells are found in the follicles and GCs, yet exhibited enhanced proliferation and migratory capacity to the chemokines CXCL12 and CXCL13. Epigenetically, CD9hi Tfh cells demonstrated a distinct transcriptional profile and chromatin architecture from their CD9lo counterpart, with an upregulation of cell cycling, PI3K, and integrin-regulated genes. Functionally, CD9hi Tfh cells had elevated VLA-4 expression and were the predominant producers of IL-21 and IFN-γ, indicating a specific role in B cell maturation and differentiation. Furthermore, deletion of CD9 did not alter Tfh cell development, but lead to their reduction of IL-21 and IFN-γ production and a decrease in overall antibody responses. Therefore, we identified that CD9hi Tfh cells are a highly functional and unique subset necessary for the promotion of antibodies during infection.
R01 AR073912
Regulation of plasmacytoid dendritic cells by ER stress-mediated metabolic responses
Authors: Chaudhary Vidyanath , Ah Kioon Marie Dominique , Hwang Sung-Min , Mishra Bikash , Lakin Kimberly , Kirou Kyriakos , Zhang-Sun Jeffrey , Wiseman Luke , Spiera Robert , Crow Mary K , Gordon Jessica , Cubillos-Ruiz Juan R , Barrat Franck J 
Published: August 2023

Abstract
Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in autoimmune diseases, including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). We report that the IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits IFN-α production by TLR7- or TLR9-activated pDCs. In SSc patients, UPR gene expression was reduced in pDCs, which inversely correlated with IFN-I–stimulated gene expression. CXCL4, a chemokine highly secreted in SSc patients, downregulated IRE1α-XBP1–controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1α-XBP1–PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.
Intestinal lamina propria stromal cells function as the target of androgens and microbiota metabolites for the prevention of lupus
Authors: Ma Jing , Harder James W , Alard Pascale , Kosiewicz Michele M 
Published: August 2023

Abstract
The gut microbiota affects autoimmune diseases including lupus. We found that female and male microbiota in NZBxNZWF1 (BWF1) mice differ. Our goal is to understand the relationship between sex, microbiota and disease. Microbiota depletion in females has no impact on disease and female microbiota does not induce disease in males; male microbiota can protect female mice from disease while castrated male microbiota loses this ability (castration induces disease and alters the microbiota in males). Intestinal lamina propria stromal cells (LPSC) can affect microbiota and immunoregulation [via regulating CD103 dendritic cell (CD103DC) development and consequently, peripheral regulatory T cells (pTregs)]. CD103DC function and pTregs are both decreased in female and castrated male mice. Endogenous androgens directly induce genes, RALDH1 and 2 (i.e., retinoic acid production), TGFB and GM-CSF, in LPSC that are critical for CD103 development. Transferred male gut microbiota induce expression of the same genes in LPSC in female recipients that we determined was not due to androgens produced by the male microbiota, since no androgen response genes, ANGTL and CHRD, were induced in highly androgen-sensitive LPSC. The male microbiota metabolomic profile differs from either female or castrated male mice, and includes the RXR agonist metabolite(s), phytol/phytanic acid, that directly induce(s) LPSC to express RALDH1 and 2, TGFB and GM-CSF. We propose that 1) endogenous androgens regulate CD103DC function and microbiota function through the LPSC in males; (2) male-modified microbiota produces metabolite(s) that may mediate protection in female recipients through the LPSC and subsequent restoration of CD103DC function and pTregs.
Funded by a TIL grant from the Alliance for Lupus Research and the NIH (R01AR067188)
Galectin-3 contributes to pathogenesis of IgA nephropathy
Authors: Chen Yi-Liang , Ka Shuk-Man 
Published: August 2023

Abstract
IgA nephropathy (IgAN) is the most common type of autoimmune glomerulonephritis that frequently progresses to end-stage renal disease. However, the molecular pathogenesis underlying IgAN remains largely unknown. This study investigated the role of galectin-3 (Gal-3), a galactoside-binding protein in IgAN pathogenesis. Two complementary mouse IgAN models, a model induced with TEPC-15 hybridoma using Gal-3 knockout (KO) mice, and a spontaneous IgAN model of “grouped” ddY (gddY) mice were employed. Gal-3 expression increased with disease severity in the glomeruli, peri-glomerular regions, and some renal tubules in both the inducible and spontaneous IgAN models. Gal-3 KO in the TEPC-15 hybridoma-induced IgAN mice significantly improved proteinuria and renal function and reduced severity of renal pathology, including neutrophil infiltration and decreased differentiation of Th17 cells from renal-draining lymph nodes, despite increased percentages of regulatory T cells. Gal-3 KO also inhibited the NLRP3 inflammasome, yet it enhanced autophagy and improved renal inflammation and fibrosis. Moreover, administration of 6-de-O-sulfated, N-acetylated low-molecular-weight heparin, a competitive Gal-3 binding inhibitor, restored renal function and improved renal lesions in passive IgAN mice. These results suggest that Gal-3 is critically involved in IgAN pathogenesis by activating the NLRP3 inflammasome and promoting Th17 cell differentiation. Therefore, targeting Gal-3 action may represent a new therapeutic strategy for treatment of this renal disease.
Nil
An essential role of iron in Tfh cell development and effector function
Authors: Scindia Yogesh , Agarwal Annanya , Gong Minghao , Abboud Georges , Mehrad Borna , Morel Laurence 
Published: August 2023

Abstract

Background
T follicular helper CD4+ cells (Tfh) are essential for maintenance of systemic lupus erythematosus (SLE) as they help germinal center B cells generate high affinity auto-antibodies. The activation of STAT3 is critical for generation of Tfh cells as it promotes the transcription of BCL6 (the essential transcription factor for Tfh cell differentiation). It is recognized that activated, proliferating SLE CD4+ T cells, contain more iron than controls. Iron binds CDK1 to accentuate JAK1 phosphorylation and activation of STAT3 in proliferating cells. Whether increased iron content of SLE CD4+ T cells augments JAK1-STAT3 signaling and their differentiation into Tfh cells has not been investigated.

Experiments
RNAseq and qPCR was used to compare iron regulatory pathways in purified Tfh cells from WT and SLE-prone mice. Labile iron (bio-active) content was measured in freshly isolated Tfh cells. The effect of iron chelator on in vitro Tfh differentiation and effector function was evaluated.

Results
Compared to WT, SLE Tfh cells displayed significant increase in genes associated with iron uptake and transmembrane iron transport. Labile iron content and CDK1 gene expression were elevated in SLE Tfh cells. Iron chelation attenuated STAT3 activation, BCL6 expression and IL-21 production in in vitro generated Tfh cells.

Conclusion
Our novel data identify an essential role of iron in Tfh cell differentiation and effector function. Increased iron and CDK1 may amplify JAK1-STAT3 signaling and potentiate Tfh cell differentiation. This can be blocked by restricting free iron availability. Understanding this aspect of Tfh cell biology in SLE may support strategies that control labile iron as potential adjunct therapy.

Supported by grants from Vifor Pharma (P0213104, P0226952) to Yogesh Scindia NIH (R01AI135128) to Borna Mehrad NIH (R01AI128901) to Laurence Morel
IL-4 role in the development of the lupus mouse model induced by non-bilayer phospholipids arrangements
Authors: Baeza Carlos Wong , Reséndiz-Mora Albany , Barrera-Aveleida Giovanna , Sotelo-Rodríguez Anahi , Galarce-Sosa Iván , Isidro-Magallán Elías , Santiago-Hernández Juan Carlos , Wong-Baeza Isabel , Baeza Isabel 
Published: August 2023

Abstract
Non-bilayer phospholipids arrangements (NPAs) are lipid molecular associations that are different from the bilayer and are transient. However, if they become stable, they can trigger a disease in mice that is similar to human systemic lupus erythematosus. NPAs can be stabilized in liposomes formed by cylindrical and conical lipids or in cell membranes by drugs such as procainamide or chlorpromazine. In wild-type BALB/c mice, this lupus model has been developed by administering liposomes with NPAs induced and stabilized with procainamide or chlorpromazine, by administering the drugs alone or by administering the monoclonal antibody H308; these last two procedures stabilize the NPAs in the membranes of mouse cells. Anti-NPAs, anti-cardiolipin, anti-histones and anti-coagulants auto-antibodies have been detected in the serum of these mice; in addition, the mice present facial lesions and alterations in the skin and kidney. In this work, we evaluated the participation of the TH2 response, through IL-4, which is its most characteristic cytokine, in the development of the NPAs-induced lupus model in mice. Wild type or IL-4 knockout BALB/c mice were administered with liposomes bearing drug-induced NPAs, the drugs alone, or anti-NPA H308 antibody to induce the lupus-like disease. IL-4 KO mice showed minor disease manifestations, compared to wild-type mice, with decreased production of anti-NPA IgG antibodies, no anti-cardiolipin, anti-histones and anticoagulant antibodies, and no kidney or skin lesions. In these mice, H308 was the only inducer of anti-NPA IgG antibodies. These findings suggest that IL-4 has a key role in the development of the murine lupus-like disease induced by NPA stabilization.
This study was supported by grants from IPN (SIP20232128, SIP20232132 and SIP20232135).
TIPE proteins control directional migration of human T cells via GPCR and lipid second messenger signaling
Authors: Sun Honghong , Yu Jiyeon , Zamani Ali , Goldsmith Jason , Etwebi Zienab , Pear Warren S , Chen Youhai H 
Published: August 2023

Abstract
Infiltration of specific tissues by circulating leukocytes is a common pathogenic mechanism of inflammatory diseases. G-protein-coupled receptors (GPCR) are essential for sensing chemokine gradients by leukocytes during immune responses. However, how leukocytes integrate site-specific directional cues such as chemokine gradients and make directional decisions in human immune cells is largely unknown. The TNFa-induced protein 8-Like (TIPE or TNFAIP8) family proteins are newly described pilot proteins that control directional migration (chemotaxis) of leukocytes to targeted tissues in mice. Without TIPE proteins, leukocytes become directionless, but the underlying mechanism remains elusive. Using siRNA and biochemical methods, we demonstrated here that two TIPE family members, TNFAIP8 and TIPE2, synergistically controlled directional migration (chemotaxis) in human CD4 T cells: TNFAIP8, through interacting with the Ga subunit of heterotrimeric G-proteins, and TIPE2, through utilizing lipid second messenger signaling by binding to phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-triphosphate (PIP3). Using site-directed mutagenesis, we identified the region of Ga that interacts with TNFAIP8, and the amino acids of TIPE2 protein crucial for its interaction with PIP2 and PIP3. We also discovered that TIPE protein membrane translocation was dependent on PIP2. Collectively, our work describes a new mechanistic paradigm of human T cells integrating GPCR and phospholipid signaling pathways to control directional migration of human immune cells. Additionally, our findings have implications for therapeutic targeting of TIPE proteins in human inflammatory and autoimmune diseases.
NIH 5R01AI136945
Extravasation of pathogenic human type 17 Th cells requires both endothelial cell-bound and non-cell bound chemokines
Authors: Parween Farhat , Singh Satya , Zhang Hongwei , Kathuria Noshin , Farber Joshua 
Published: August 2023

Abstract
Extravasation of pro-inflammatory T cells is critical for their effectiveness in host defense and for mediating tissue damage in immune-mediated disease. These cells co-express multiple chemokine receptors and understanding the activities of individual receptors in extravasation is essential for exploiting the chemokine system for therapeutic benefit – either to block or enhance the trafficking of these cells into sites of inflammation. CCR6 is expressed on all human Th17 cells, and we found that CCR6+CCR2+ cells are enriched both in cells that express a pathogenic Th17 signature, including the ability to produce GM-CSF and IFNγ, and are unusually efficient at transendothelial migration (TEM). Ligands for CCR6, CCR5 and CXCR3 were secreted by and bound to endothelial cells activated with TNFα and IFNγ, and these receptors could all mediate firm arrest of CCR6+CCR2+ cells under flow - but could not mediate TEM. TEM required CCR2, whose ligands, CCL2, CCL7 and CCL8, were all secreted by activated endothelial cells but failed to bind to endothelial cell surfaces. Chemokines were secreted from the basal as well as the apical sides of endothelial cells. Pre-treating CCR6+CCR2+ cells with CCL2 or transducing endothelial cells to express a surface-bound CCL2-CXCL9 chimera led to both CCR2-mediated arrest and, importantly, inhibition of TEM. Taken together, our data suggest that while arrest requires endothelial surface-bound chemokine, TEM requires a transendothelial gradient maintained by the rapid dilution of non-bound luminal chemokine by flow. Consequently, mediating arrest versus TEM are not inherent, but nonetheless mutually exclusive activities of receptors that depend, respectively, on binding vs. non-binding chemokines.
NIH