bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotypic characterization of mice carrying a PTPN22 single nucleotide polymorphism associated with autoimmunity in humans (47.13)
Authors: Beauchemin Hugues , Piccirillo Ciriaco , Peterson Alan , Polychronakos Constantin 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is a strongly heritable autoimmune disease due to the destruction of pancreatic β-cells by self-reactive T-cells. The third strongest genetic locus for T1D involves a single-nucleotide polymorphism (SNP) causing an arginine(R) to triptophan(W) substitution at codon 620 (620R&gt;W) in PTPN22, the gene encoding the tyrosine phosphatase LYP, an important negative regulator of T-cell receptor (TCR) activation. However, the cellular effects of the 620R&gt;W risk allele remain controversial, as different studies report either a gain or a loss of function in its ability to inhibit TCR signaling. To study this variant in an animal model, we created a knock-in mouse by introducing the 620R&gt;W substitution in, the murine LYP orthologue, PEP encoded by Ptpn22. The knock-in analyzed on the autoimmune-resistant C57Bl/6 background showed a mild but significant increase in CD4+ helper T-cell activation and proliferation upon weak TCR activation. Conversely, upon strong TCR stimulation, the tendency seemed to be reversed as the 620W allele showed a slightly decreased responsiveness compared to the 620R allele. Phenotypic analysis of other immune cellular compartments, including memory T cells, showed no significant difference between genotypes. There was no evidence of autoimmunity in this genetic background. This dependence of allelic effect on the strength of the TCR signal may reconcile previous observations and indicate a complex role of R620&gt;W in autoimmunity.
A spontaneous mutation leads to impaired regulatory T cell functions and inflammatory bowel disease (47.19)
Authors: Chabod Marianne , Pedros Christophe , Lamouroux Lucile , Vergnolle Nathalie , Andreoletti Olivier , Saoudi Abdelhadi , Fournie Gilbert , Dejean Anne S. 
Published: January 2023

Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders affecting genetically predisposed hosts. The current challenge lies on the identification of the causal gene variants and of their contribution to disease physiopathology. We identified a spontaneous mutation in Brown-Norway rats localized in a 1.2 cM locus containing only 6 genes. We showed that rats bearing the mutation present a CD4 T cell lymphopenia that originates in the thymus and is T cell autonomous. Interestingly, mutated rats spontaneously develop inflammatory lesions that share many pathological features with Crohn’s disease. Histological analysis revealed multifocal cellular infiltrations mainly composed of polymorphonuclear cells, macrophages and presence of granuloma. These lesions are characterized by increased myeloperoxidase activity and proinflammatory cytokine levels such as IL-1β, IL-2, IL-6, IL-17, TNF, CCL2 and CCL3. Further functional studies revealed an impaired suppressive activity of regulatory CD4 T cells (Treg) from mutated rats. IBD development is likely due to this defect, since complementation of mutated rats with wild-type Treg decreased disease incidence and severity. Thus, we report that a gene or a set of genes included within the 1.2 Mb interval should be considered henceforth as a candidate susceptibility locus for IBD and that it may act through its effect on Treg suppressive function and therefore on immune system homeostasis.
Reduced expression of cyclin-depedent kinase inhibitor Cdkn2c reduced IL-2 production by CD4+ T cells expressing the murine NZB-derived Sle2c1 susceptibility locus (47.22)
Authors: Xu Zhiwei , Potula Hari-Hara , Vallurupalli Anusha , Morel Laurence 
Published: January 2023

Abstract
Sle2c1 is a sublocus from the NZB-derived Sle2 locus found in the NZM2410 lupus-prone mouse. In addition to expanding the peritoneal cavity B1a cells, Sle2c1 significantly reduced IL-2 production by activated CD4+ T cells in vitro and is associated with a reduction of the Treg compartment, especially in Fas-deficient mice. The characterization of three Sle2c1 recombinants mapped the IL-2 deficiency to a short interval on chromosome 4 that contains the Cdkn2c gene. Cdkn2c encodes for p18INK4c (p18), a cyclin-dependent kinase inhibitor that regulates G1 cell cycle arrest. We have found a novel SNP in the Cdkn2c promoter that is associated with a significantly reduced expression of this gene in CD4+ T cells. Activated CD4+ T cells from B6.p18-/- mice produced significantly less IL-2 than B6 controls, demonstrating that a dysregulated cell cycle interferes with IL-2 production. Interestingly, we have also found that p18 reduced expression, either in B6.Sle2c1 or B6.p18-/- mice, is also associated with an expansion of the B1a cells compartment. Overall these results show that a dysregulated cell cycle affects CD4+ T cell and B cell homeostasis and is associated with lupus susceptibility, either through an expansion of the b1a cells, a reduced IL-2 production, or both.
The de novo revision of TCRα but not TCRβ is responsible for generating autoantibody-inducing CD4+ (aiCD4+) T cell that causes systemic autoimmunity, i.e., SLE (47.26)
Authors: Uto Kenichi , Tsumiyama Ken , Takimoto Mai , Shiozawa Shunichi 
Published: January 2023

Abstract
Objective: The induction of autoantibody-inducing CD4+ (aiCD4+) T cell after repeated immunization with antigen is the key for the induction of autoantibodies including anti-dsDNA antibody and immune tissue injury in SLE in our ‘self-organized criticality theory’. Here we investigated the mechanism for generating aiCD4+ T cell. Methods: BALB/c mice were immunized 8x with staphylococcul enterotoxin B (SEB). RAG1/2, TdT and pTα were detected using RT-PCR. Expression of GFP was studied in RAG-1/GFP knock-in mice. The rearranged intermediates of TCRα joining regions from 1 to 61 and all TCRβ variable and diversity regions were detected using LM-PCR. Histone modification of TCR loci was examined using ChIP assay. Results: RAG1/2, TdT pTα and were re-expressed in splenic T cell and expression of RAG1 gene was confirmed in vivo in RAG1/GFP knock-in mice after immunization 8x with SEB. The rearranged intermediates of TCRα joining region 12 were selectively induced in splenic Vβ8+CD4+ T cell after immunization 8x with SEB. Instead, rearranged intermediates of all TCRβ regions were never observed. The histone H3 of the TCR loci of splenic CD4+ T cell was heavily acetylated and trimethylated to the extent identical to thymocytes. Conclusion: As to the reason why TCRα gene was solely rearranged, since TCR gene loci were found to be always accessible and ready to TCR revision, we assume that TCR revision related to autoimmunity may be governed structurally by TCRβ molecule.
The TNFAIP3 haplotype associated with SLE leads to altered A20 expression and enhanced cellular activation of primary human B cells (47.6)
Authors: Humphrey Mary Beth , Templeton Amanda , Hu Yanqing , Wen Daniel , Gaffney Patrick 
Published: January 2023

Abstract
TNFAIP3 encodes an ubiquitin modifying enzyme, A20, required to limit NF-kB activity downstream of TLR and TNF receptors. We have recently identified a novel TT&gt;A polymorphism ~25 kb downstream of TNFAIP3 as the best candidate polymorphism responsible for the association of TNFAIP3 with SLE (Adrianto, Wen, Templeton, et al. Nature Genetics, in press). Here we investigate the functional consequence of expression of the risk haplotype defined by the minor -/A allele at position chr6:138,271,732-733 in peripheral B cells isolated from subjects expressing one copy of the risk haplotype compared to controls. With IRB approval, blood samples from 11 paired risk and controls were collected through the Large Lupus Family Registry at OMRF. Resting B cells from risk samples had significantly less A20 expression compared to controls. CD40L stimulation significantly increased A20 expression in control samples but not risk samples. CD40L induced higher NF-kB p52 activation and induced significantly more CD86 expression in risk compared to control samples. Overall, these results confirm the risk haplotype defined by the TT&gt;A polymorphism confers functional consequences of lower A20 expression, enhanced NF-kB signaling and increased cellular activation of primary B cells. Inappropriate B cell activation as a result of reduced TNFAIP3 expression in cells carrying the TT&gt;A variant likely contributes to increased autoimmunity and SLE risk.
Promigratory secreted protein Collagen triple helix repeat containing 1 is involved in sex-biased regulation of inflammatory arthritis (47.8)
Authors: Shekhani Mohammed , Ramez Mohamed , Forde Toni , Lyons Elizabeth , Lindner Volkhard , Adarichev Vyacheslav 
Published: January 2023

Abstract
Molecular mechanisms of sex disparities in autoimmune inflammatory diseases, including rheumatoid arthritis (RA), are not well defined. To model human disease, collagen antibody-induced arthritis (CAIA) was induced in BALB/c.DBA/2-Pgia8 congenic mice. Chromosome interval Pgia8 showed anti-inflammatory effect in congenic males, while females exhibited CAIA that was similar to wild-type mice. Transcriptome analysis indicated that expression of three locus-specific genes was tightly correlated (r=0.87-0.91) with inflammation: Collagen triple helix repeat containing 1 (Cthrc1), R-spondyn 2 and Syndecan 2. The link between Cthrc1 and arthritis was reproduced in F1(BALB/c x FVB-Tg[Cthrc1]) mice, since mice overexpressing Cthrc1 transgene showed 1.2-1.4-fold stronger inflammation than tg-negative F1 hybrids. Importantly, naïve F1(BALB/c x FVB-Tg[Cthrc1]) mice exhibited pre-inflammatory phenotype of neutrophilia (30% upregulated, p&lt;0.014) accompanied with monocytopenia (50% downregulated, p&lt;0.025) in peripheral blood. Cellular mechanisms of arthritis regulation via Cthrc1 were addressed using immunodetection techniques. Present study indicates that promigratory protein Cthrc1 effects hematopoiesis and is also implicated in sex-biased regulation of inflammatory arthritis.
The importance of be(ginn)ing naïve: implications for cancer immunotherapy (48.18)
Authors: Cieri Nicoletta , Camisa Barbara , Provasi Elena , Magnani Zulma , Mondino Anna , Bondanza Attilio , Bonini Chiara 
Published: January 2023

Abstract
Manipulation required to expand or engineer tumor-specific lymphocytes often induces terminal differentiation, resulting in poor in vivo efficacy. We hypothesized that initial targeting of Naive T cells (TN) could overcome this limitation. We activated and efficiently transduced FACS-sorted TN, TCM and TEM cells by viral vectors. Activation of TN with anti CD3/CD28 beads resulted in a predominant population of highly proliferative CD45RA+CD62L+CCR7+ T cells, that did not produce γIFN nor cytotoxic molecules and required IL7 and IL15 for their generation and maintenance. Manipulated-TN were post-mitotic, and expressed CD45RO, CD122, CXCR3 and CD95. Compared to manipulated-TCM and -TEM, naïve-derived T cells expressed higher levels of CD127, c-Kit and CXCR4 and lower levels of CCR5, HLA-DR and PD-1. To verify their differentiation potential, TN TCM and TEM were transduced to express a WT1-specific TCR and stimulated with WT1 peptide. In this context, TN expanded at higher numbers, differentiated into both CD45RA-CD62L+ and CD45RA-CD62L- cells and generated a mixed population of CD127± cells. When infused in NOD/Scid mice, manipulated TN showed a degree of xenoreactivity comparable to that of unmanipulated lymphocytes. In contrast to manipulated TCM cells, manipulated TN cells engrafted in secondary and tertiary recipients indicating that persistence, self-renewal abilities and expansion potential are preserved in this novel T cell subset after genetic manipulation.
Tri-component MUC1 glycopeptide vaccine induced both humoral and cellular immune responses in MUC1.Tg mice with MMT tumor. (48.20)
Authors: Lakshminarayanan Vani , Thompson Pamela , Wolfert Margreet , Bradley Judy , Pathangey Latha , Madsen Cathy , Cohen Peter , Boons Geert-Jan , Gendler Sandra 
Published: January 2023

Abstract
Effective immunotherapy for cancer depends on both cellular and humoral immune responses to tumor antigens. MUC1, which is expressed at increased levels on breast cancer, also exhibits altered glycosylation that contributes to the formation of novel antigens. The identification of MHC class I and II binding peptides derived from tumor-associated MUC1 has facilitated the development of MUC1 based cancer vaccines. We have shown that the MHC class I binding epitopes from MUC1 tandem repeat, when given as emulsification with adjuvants, has always resulted in strong cellular response with no antibody response. It is possible that better immunogenicity would be obtained using glycopeptides more representative of the novel forms of MUC1 as seen in cancer to which individuals may be less tolerant and that direct linking of the vaccine components would result in a superior immune response than delivering them as a mix. Here we show that a three-component vaccine composed of a TLR2 agonist, a helper epitope and a T cell epitope, which is also a B cell epitope, derived from the MUC1 can break tolerance and elicit both humoral and cellular immune responses. Immunization with the MUC1 glycopeptide vaccine led to a significant reduction in tumor burden compared to mice treated with adjuvants only and empty liposomes. The tri-component vaccine activated MUC1 glycopeptide-specific cytotoxic CD8+ T cells and elicited robust titers of IgG antibodies that lyse relevant tumor cells by ADCC.
Interaction between tumor and myeloid cells induce/expand Th17 cells in malignant gliomas (48.28)
Authors: Parajuli Prahlad , MIttal Sandeep , Chinni Sreenivasa , Lum Lawrence , Thakur Archana , Guthikonda Murali 
Published: January 2023

Abstract
Th17 cells, a recently discovered inflammatory T cell subtype, have been reported in several tumors, where they are implicated with either pro- or anti-tumor activity, depending on the tumor type. Th17 cells have not been studied with respect to brain tumors. We have been studying the mechanism of induction and role of Th17 cells in malignant gliomas using primary tumor as well as glioma cell lines. We report here that: 1) There is considerable prevalence of Th17 cells and myeloid (CD11b) cells among glioma-infiltrating immune cells; 2) Glioma cells express the cytokines TGF-β1 and IL-6, while the infiltrating myeloid cells express IL-1β and IL-23; 3) Naïve T cells cultured with anti-CD2/CD3/CD28-loaded microbeads in the presence of glioma culture supernatants differentiate into Th17 cells, which is inhibited by antibodies to TGF-β1 and IL-6; 4) Supernatant from glioma-monocyte co-culture generates significantly higher frequency of Th17 cells compared to glioma supernatant, which is abrogated by antibodies to IL-1β and IL-23. Moreover, 5) Th17 cells generated in the presence of supernatant from glioma-monocyte co-culture have low IFN-γ and high IL-10 expression, suggesting that glioma-associated Th17 cells may be immune suppressive. Further studies on the mechanism of tumor-infiltration, developmental pathways and pro-/anti-tumor functions of Th17 cells will provide rationale for developing novel adjuvant immunotherapeutic strategies for malignant gliomas.
Thymic stromal lymphopoietin mediates breast cancer progression and metastasis (48.9)
Authors: Bodogai Monica , Olkhanud Purevdorj , Rochman Yrina , Malchinkhuu Enkhzol , Wejksza Katarzyna , Gress Ronald , Hesdorffer Charles , Leonard Warren , Biragyn Arya 
Published: January 2023

Abstract
Breast cancer escape and metastasis is an active process that requires inflammation and participation of immune cells. We have previously reported that this is a primary tumor-controlled process which activates lungs to produce CCL17 and CCL22 to facilitate lung metastasis together with the recruitment of CCR4+ regulatory T cells (Tregs). To understand the mechanism of this process, we performed expression array analysis in both metastatic and non-metastatic cancer cells and found that metastatic cells produced thymic stromal lymphopoietin (TSLP), an IL-7-like type 1 inflammatory cytokine that is often associated with the induction of Th2-type allergic responses in the lungs. Moreover, TSLP was also abundantly expressed in variety of human solid tumors, including breast, lung, colon and ovarian cancers. To gain further insights into the role of TSLP in cancer progression, we have blocked TSLP expression in cancer cells and found that TSLP is required for efficient breast cancer escape and metastasis. Moreover, utilizing adoptive transfer studies in TSLPR deficient mice, we demonstrated that by targeting CD4+ T cells to induce Th2-type inflammatory responses, cancer-produced TSLP promoted cancer escape. Taken together, our data indicate that TSLP is an important factor that needs to be controlled to effectively combat with cancer escape.
Early cytokine dysregulation contributes to mortality during lethal influenza infection. (49.18)
Authors: Brown Deborah , Vogel Alexander , Condon Shirley 
Published: January 2023

Abstract
Recent studies have suggested that pandemic influenza viral strains induce high pro-inflammatory cytokine levels in the lung that may contribute to increased mortality. However, the mechanisms linking highly virulent virus infection and mortality have not been fully elucidated. Here we compare a sublethal dose of highly pathogenic H1N1 virus, A/Puerto Rico/34/8 (PR8) with a lethal dose to determine the extent by which viral load affects inflammatory responses in the lung. We observed a 5-10 fold increase in viral load that correlated with a 10 fold increase in TNF-α, IL-1β and MIP-1α secretion in lethally infected mice compared to sublethally infected mice at day 2 post infection (p. i.). Surprisingly, this difference was not apparent at later time points after infection indicating early cytokine dysregulation may contribute to mortality. IL-6, MCP-1 and MIP-1β were also upregulated at day 2 p. i. and peaked at day 6 suggesting sustained levels of certain cytokines may also contribute to pathology. Furthermore, we find that RIG-I and TLR-3 are upregulated in CD45- epithelial cells leading to high expression of IFN-β and IL-6 while TLR-7 and TLR-9 are highly upregulated in CD45+ immune cells correlating with expression of TNF-α. Thus, differential PRR usage and cytokine secretion may be a contributing factor in the balance between protective immunity and pathogenicity.
Memory CD4 T cells drive emergence of viral escape mutants during influenza challenge in the absence of CD8 T cells and B cells (49.6)
Authors: McKinstry Karl , Strutt Tara , Swain Susan 
Published: January 2023

Abstract
How T cells contribute to protection against influenza virus during heterosubtypic challenge is not fully understood. Here we investigate the potential for memory CD4 T cell-mediated protection against influenza. We find that transfer of influenza-primed, Th1-, or Th17-polarized T cell receptor transgenic memory CD4 T cells recognizing influenza can completely protect otherwise naïve hosts against an otherwise lethal influenza challenge in the absence of either B cells or CD8 T cells. However, in the absence of both B cells and CD8 T cells, monoclonal memory CD4 T cells fail to clear virus, leading to a chronic infection characterized by high viral titers, systemic inflammation, and ultimately death. During such chronic infection, memory CD4 T cells exert substantial selective pressure on the challenge virus as we demonstrate the emergence of T cell receptor epitope-specific viral escape mutants. In contrast to the failure of monoclonal memory CD4 T cells to clear influenza in the absence of CD8 T cells and B cells, transfer of polyclonal memory CD4 T cells isolated from influenza-primed mice completely clear virus. These studies demonstrate that memory CD4 T cells can not only provide protection against influenza, but also that they can exert substantial selection pressure. Furthermore, our results support the concept that heterosubtypic immunity to influenza can take several forms.
Complementary functions of FADD and RIP1 critical for embryogenesis and T cell proliferation (50.8)
Authors: Zhang Jianke 
Published: January 2023

Abstract
FADD is a common adaptor shared by several death-receptors (DRs) for signaling apoptosis through recruitment and activation of caspase 8. DRs are essential for immune homeostasis, but dispensable during embryogenesis. Surprisingly, FADD-/- mice die in utero and conditional deletion of FADD leads to impaired lymphocyte proliferation. How FADD regulates embryogenesis and lymphocyte responses has been a long standing enigma. FADD could directly bind to RIP1, a serine/threonine kinase which mediates both necrosis and NF-kB activation. Our data indicate that FADD plays a role in regulating RIP1 expression and necrosis in embryos. To investigate a potential in vivo functional interaction between RIP1 and FADD, we generated mice lacking both FADD and RIP1and performed analyses of the resulting double knockout mutant mouse embryos and lymphocytes. The data from these studies have revealed an unexpected cell type-specific interplay between FADD and RIP1, which is critical for the regulation of apoptosis, necrosis and NF-kB activation during embryogenesis and lymphocyte function.
Adenosine 2A Receptor agonists-induced tolerogenic dendritic cell protected kidney from ischemia/reperfusion injury (52.13)
Authors: Li Li , Huang Li-ping , Song Steven , Ye Hong , Porcelli Steven , Okusa Mark 
Published: January 2023

Abstract
NKT cell activation initiates the kidney ischemia/reperfusion injury (IRI) immune response. There are no effective treatments available on acute kidney injury (AKI) to date. DCs represent a new and promising immunotherapeutic approach for autoimmune diseases. Adenosine 2a receptor (A2aR) agonist, ATL313, protected kidney from IRI. We hypothesize that ATL313 programs DCs into tolerogenic DCs during a-galactosylceramide (aGC) priming in vitro, which protected the kidney from IRI by suppressing NKT cell activation. Both kidney pedicles were clamped in B6 mice for 24 mins and then released for 24 hrs. BMDCs were cultured and loaded with aGC(0.1nM) w or w/o ATL313(1nM). Cells were adoptively transferred to naive WT mice 2 days prior to the surgery. ATL313-treated aGC loaded WT DC (WT DC-aGC-ATL) significantly protected kidney IRI with lower plasma creatinine compared with DC-aGC control (P&lt;0.001), which was not seen in A2aRKO DC-aGC-ATL treated mice (P&gt;0.05). Mice receiving WT DC-aGC had significantly increased plasma IFN-g level (P&lt;0.01), while mice receiving WT-DC-aGC-ATL had significantly lower level (P&lt;0.01). ATL313 has no effect on CD1d/aGC complexes (L363) on DCs, but decreased IA, CD86 and CD40 expression on WT not A2aRKO DC-aGC. ATL313-induced tolerogenic DCs have increased IL-10 mRNA expression compared with DC-aGC (P&lt;0.05). A2aR agonist-induced toerogenic DCs is a unique and potent cell-based strategy to attenuate IRI by blocking DC-NKT cell immunological synapses.