bluuebunny/crossref_metadata_2025_split huggingface dataset:
The essential role of IL-7 signalling in CD8+ T-cell activity (57.17)
Authors: Crawley Angela , Agatha Vranjkovic , McGuinty Mikki , Faller Elliott , MacPherson Paul , Angel Jonathan 
Published: January 2023

Abstract
Anti-viral CD8+ T-cell responses become impaired in HIV infection in part due to decreased T-cell survival, function and memory cell development; aspects mediated largely by interleukin-7 (IL-7). In progressive HIV infection, decreased T-cell expression of the IL-7 receptor α (CD127) and impaired IL-7 signalling, despite increased IL-7 production, may contribute to failing T-cell activity. Here we examine the effects of IL-7 on a panel of signalling pathways and investigates how IL-7 signalling pathways are associated with IL-7-related activities in CD8+ T-cells. Low concentrations of IL-7 (10 pg/ml) are capable of inducing maximum activation of the Jak-STAT and PI3K signalling pathways, while higher concentrations (500-1000 pg/ml) were required to induce Bcl-2 production and glucose uptake. Even higher concentrations of IL-7 (10,000 pg/ml) were needed to induce cell proliferation and perforin release. Inhibition of Jak activation reduced IL-7-induced Bcl-2, perforin production and proliferation. The activation of intracellular signalling pathways by IL-7 in human CD8+ T-cells and how they are associated with IL-7-induced functions has been extensively studied. Furthermore, the kinetic and optimal concentrations of IL-7 required for the induction of these functional outcomes suggest a complex control of IL-7-associated functions. This may provide insight in immune restoration therapies in HIV infection, where IL-7 signalling and functions are impaired.
Detection of a point mutation in IL12/23 receptor beta 1 chain in a Mexican patient with uncommon clinical feature. (58.5)
Authors: Ramirez Alejo Noe , Estrada Garcia Iris , Blancas Galicia Lizbeth , Espinosa Rosales Francisco , Santos Argumedo Leopoldo 
Published: January 2023

Abstract
Mendelian susceptibility to mycobacterial disease (MSMD) is a heterogenous syndrome. The clinical characteristics include repetitive local infection and in some cases dissemination. In this work we analyzed a 5 years old boy with an uncharacterized mycobacterial infection. His parents are first degree cousins. Blood samples were collected and cultured 48 hours with medium, BCG or BCG+IL-12. Supernatants were assayed for IFN-γ by ELISA. PBMC were cultured with PMA-Ionomicyn and IL12R was measured by flow cytometry. We found low production of IFN γ after stimulation with BCG+IL12 that seems to correlate with an IL-12R defect. Flow cytometry showed a decrease of IL-12RB1 expression. Sequencing revealed a point mutation (A182T), which generates E61G change in the extracellular domain. Furthermore, the uncommon clinical features in this case might suggest another primary immunodeficiency.
Augmented Th2 response and liver fibrosis in mice lacking the chitinase like protein, BRP-39 (58.9)
Authors: Ramalingam Thirumalai , Barron Luke , Mentink-Kane Margaret , Cheever Allen , Humbles Alison , Kolbeck Roland , Wynn Thomas 
Published: January 2023

Abstract
The mouse Breast Regression Protein 39 (BRP39; Chi3l1) is a chitinase like protein but lacks enzymatic activity. Recently it was shown that mice lacking BRP39 displayed significantly impaired Th2 response during allergic airway disease. We sought to examine if the absence of BRP39 would affect the generation of protective and pathogenic Th2 responses following helminth infections. In a model of Schistosoma mansoni egg induced pulmonary granuloma formation, naive BRP39KO animals developed weaker Th2 response upon egg embolization. The Th2 responses were restored to WT levels if pulmonary granulomas were elicited in antigen primed (secondary granuloma) animals. However, the size of secondary egg granulomas remained significantly smaller in the KO animals, suggesting a role for BRP39 in regulation of pulmonary granuloma response. In contrast, following infection with S. mansoni cercariae, BRP39KO animals manifested larger hepatic granulomas and significantly exacerbated liver fibrosis and showed an increased prevalence of CD4+ cells making IL-5 and IL-13 among the granuloma leukocytes. Furthermore, Nippostrongylus brasiliensis infected BRP39KO mice displayed no defect in worm expulsion suggesting normal Th2 response in the gut. Thus, these studies reveal that the defectiveTh2 response in the absence of BRP39 is a transient phenomenon and introduce the possibility that BRP39 could negatively regulate Th2 responses in a chronic setting and in a tissue specific manner.
Transgenic human IL-10 expression by CD4+ T cells is associated with resistance to colitis in Il10-/- mice (59.11)
Authors: Bream Jay , Ramakrishnan Amritha , Wang Fengying , Brayton Cory , Ranatunga Dilini 
Published: January 2023

Abstract
Studies in mice suggest that the cellular source of the immunoregulatory cytokine IL-10 plays a key role in determining susceptibility to various infectious and autoimmune diseases. To better understand cell-specific human IL-10 (hIL-10) expression we generated a hIL-10 transgenic mouse using a bacterial artificial chromosome (hIL10BAC). Human IL-10 is biologically active in the mouse, and by reconstituting Il10-/- mice with the hIL10BAC we can evaluate the effects of human IL-10 regulation in vivo. We found that the hIL10BAC rescues Il10-/- mice from helicobacter-induced colitis as evidenced by histopathology scores of inflammation and a failure to develop rectal prolaspe. Aberrant proinflammatory cytokine mRNA expression in the colons of Il10-/- mice was reduced in Il10-/-/hIL10BAC mice. Likewise, the percentages of IL-17-expressing CD4+ T cells in the ileal and colonic lamina propria were normalized to WT levels in Il10-/-/hIL10BAC mice. In searching for cellular sources of hIL-10 we found that hIL-10 expression was enriched specifically within the colonic lamina propria and these cells were CD4+CD25+Foxp3+ T cells. Adoptive transfer of CD4+ Il10-/-/hIL10BAC T cells protected Rag1-/- mice from wasting disease using a T cell transfer model of colitis. These data combined with previous results from our laboratory suggests that human IL-10 expression in various CD4+ T cell subsets is under different regulatory constraints.
Transfer of IgG in the female genital tract by the FcRn confers protective immunity to vaginal infection (59.3)
Authors: Zhu Xiaoping , Li Zili , Palaniyandi Senthilkumar , Zeng Rongyu , Tuo Wenbin , Roopenian Derry 
Published: January 2023

Abstract
IgG is a major Ig subclass in mucosal secretions of the human female genital tract, where it predominates over the IgA isotype. Despite the abundance of IgG, surprisingly little is known about where and how IgG enters the lumen of the genital tract and the exact role local IgG plays in preventing sexually transmitted diseases. We demonstrate here that the FcRn is expressed in female genital tract epithelial cells of humans and mice and binds IgG in a pH dependent manner. In vitro we show that FcRn mediates bidirectional IgG transport across polarized human endometrial HEC-1-A monolayers and primary human genital epithelial cells. Furthermore, endosomal acidification appears to be a prerequisite for FcRn-mediated IgG transcytosis; IgG transcytosis was demonstrated in vivo by translocation of systemically administered IgG into the genital lumen in WT but not FcRn-KO mice. The biological relevance of FcRn-transported IgG was demonstrated by passive immunization using HSV-2-specific polyclonal serum, which conferred significantly higher protection against intravaginal challenge infection by the HSV-2 186 strain in WT mice than in FcRn-KO mice. These studies demonstrate that FcRn-mediated transport is a mechanism by which IgG can act locally in the female genital tract in immune surveillance and in host defense against sexually transmitted diseases.
Macrophage migration inhibitory factor promotes central nervous system pathology through local microglial activation and macrophage trafficking (60.3)
Authors: Cox Gina Mavrikis , Alexander J. , Kithcart A. , Williams J. , Smith K. , Shawler T. , Guan Z. , Satoskar A. , Popovich P. , Whitacre C. 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). It is reported that cerebrospinal fluid from MS patients during relapse contains higher levels of MIF than samples collected during remission. While the potent pro-inflammatory properties of MIF are well established, the precise contribution to neuroinflammation is not well defined. We have previously shown that despite their ability to generate pathogenic T cells, MIF-/- mice fail to develop experimental autoimmune encephalomyelitis (EAE), and have reduced CNS pathology. These findings suggest that MIF acts within the CNS to potentiate disease progression. We observed that MIF-treated microglia upregulate inflammatory mediators associated with MS and EAE including IL-1, IL-6, TNF-α, iNOS, and CCL2, and exhibit morphological changes consistent with activation. We extended these findings in vivo, performing stereotactic spinal microinjection of rMIF into naïve mice, which resulted in targeted microglial reactivity and cellular infiltration. To determine the role of MIF in the CNS during EAE, we examined the ability of rMIF spinal microinjection to restore CNS pathology in MIF-/- mice. Notably, rMIF microinjection was sufficient to restore CNS pathology in EAE-resistant MIF-/- mice following induction of EAE. Taken together, these studies implicate MIF as a CNS inflammatory mediator that may contribute to the development and maintenance of MS lesions.
Hapten application to the skin induces an inflammatory program directing hapten-primed effector CD8 T cell interaction with hapten-presenting endothelial cells (60.6)
Authors: Kish Danielle , Volokh Nina , Baldwin William , Fairchild Robert 
Published: January 2023

Abstract
Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to hapten sensitization and challenge of the skin. Effector CD8 T cell recruitment into the skin parenchyma to elicit CHS to hapten challenge requires prior CXCL1-directed neutrophil infiltration within 3-6 h after challenge and is dependent on IFN-γ and IL-17 produced by the hapten-primed CD8 T cells. Mechanisms directing CD8 T cell localization and activation in the challenge site to induce CXCL1 production in response to 2, 4-dinitrofluorobenzene were investigated. Both TNFα and IL-17, but not IFN-γ, mRNA was detectable within 1 h of hapten challenge of sensitized mice and increased thereafter. Expression of ICAM-1 was observed by 1 h after challenge of sensitized and non-sensitized mice and was dependent on TNFα. The induction of IL-17, IFN-γ and CXCL1 in the challenge site was not observed when ICAM-1 was absent or neutralized by specific antibody. During the elicitation of CHS, endothelial cells (EC) expressed ICAM-1 and produced CXCL1. EC isolated from challenged skin of naïve and sensitized mice had acquired the hapten and the ability to activate hapten-primed CD8 T cell cytokine production. These results indicate that hapten application to the skin of sensitized animals initiates an inflammatory response promoting hapten-primed CD8 T cell localization to the challenge site through TNFα induced ICAM-1 expression and CD8 T cell activation to produce IFN-γ and IL-17 through EC presentation of hapten.
Migrating out of the zone: the role of P-selectin glycoprotein ligand-1 on T follicular helper cell movement (60.8)
Authors: Hernandez Sairy , Weinstein Jason , Steiner Laurie , Bertino Sarah , Poholek Amanda , Gallagher Patrick , Craft Joseph 
Published: January 2023

Abstract
Follicular helper T cells (TFH) are essential for the formation of germinal centers (GC) during a T-dependent immune response, providing critical factors that promote memory B cell and plasma cell development. Differentiation and function of TFH cells are dependent upon their movement out of the T cell zone and into the B cell follicle, a process regulated by modulation of chemokine receptor expression. Here we explore the role of the secondary lymphoid organ homing molecule, PSGL1, as a T zone retention signal, demonstrating that its downregulation on TFH cells is necessary for their migration out of the T cell zone and into the follicle. Upon immunization of PSGL1-intact and -deficient mice, we found that the latter had an increase in TFH cells and GC B cells in lymph nodes and spleen, and enlarged GCs with enhanced numbers of T cell infiltrates, compared to wild type controls. Following adoptive transfer, a higher frequency of PSGL1-deficient T cells localized to B cell follicles and GCs compared to controls, whereas retroviral over-expression of PSGL1, preventing its downregulation, led to exclusion of T cells from follicles and GCs. Consistent with these observations was the finding in chromatin immunoprecipitation assays that Bcl6, the lineage-specific transcription factor of TFH cells, bound the psgl1 gene. These data reveal that PSGL1 downregulation on TFH cells is required for their migration within lymphoid organs and function during a TD immune response.
Type I IFN-mediated reversal of TLR tolerance in antigen presenting cells (61.13)
Authors: Poovassery Jayakumar , Bishop Gail 
Published: January 2023

Abstract
Many synthetic ligands for TLRs, especially TLR 7/8 and 9 agonists, induce potent innate and adaptive immune responses and are thus under consideration as vaccine adjuvants and as anti-cancer agents. In addition, TLR7 and 9 agonists are potent type I IFN inducers and play critical roles in defense against viral infections. Many TLR-mediated responses in antigen presenting cells are also modulated by Type I IFN receptor signals. However, the precise molecular mechanisms involved in cooperation between these two receptors are not clear. We have previously shown that repeated stimulation through TLR7 can induce a state of hyporesponsiveness (TLR tolerance) in B cells characterized by severe defects in major signaling pathways. In this study, we investigated whether simultaneous signals through type I IFN receptor can reverse tolerance in B cells and dendritic cells. We found that signals through type I IFN receptor can prevent and reverse TLR tolerance in mouse and human B cells and in mouse bone marrow derived dendritic cells. The reversal of hyporesponsiveness was associated with activation of p38 and ERK1, 2 and c-Jun phosphorylation. Moreover, Type I IFNR-mediated reversal of tolerance was dependent on the PI3K/Akt/mTOR pathway. A better understanding of how these important signaling pathways interact can significantly increase our ability to develop better vaccine adjuvants and immunotherapeutic agents against cancer.
CD1d expression by dendritic cells and CD40L or ICOS expression by NKT cells is dispensable for NKT-enhanced humoral immunity (61.16)
Authors: Lang Mark , Shah Hemangi , Joshi Sunil , Kovats Susan , Lang Gillian , Devera T. 
Published: January 2023

Abstract
CD1d-binding glycolipids have potent adjuvant effects on T-dependent humoral immune responses to co-administered protein antigen. We reported previously that cognate interactions between CD1d expressed on B cells and the T cell antigen receptor of natural Killer T (NKT)was critical for the adjuvant effect of the CD1d ligand α-galactosyl ceramide (α-GC). We have therefore tested the hypothesis that CD1d-expressing dendritic cells contribute to NKT-enhanced antibody production and that NKT cells provide co-receptor-mediated B cell help. Using bone marrow chimera approaches, we demonstrate that CD1d-expression by dendritic cells as well as CD40L and ICOS expression by NKT cells are dispensable for the adjuvant effects of α-GC. This reinforces the concept that the primary mode of NKT activation is through CD1d-expressing B cells and indicates that NKT cells utilize mechanisms distinct from that of helper T cells to provide specific B cell help.
Antigen altered idiotype induces immune regulation implications for cancer, autoimmunity and AIDS (61.17)
Authors: Williams R Michael 
Published: January 2023

Abstract
Antigen altered idiotype regulates specific immune responses. Mendelian segregation of a given +/- phenotype defines an immune response gene (IR-X) . Autoimmunity producing anti-self clones must be eliminated or specifically suppressed, so a large portion of the antigenic repertoire resembles allogeneic MHC molecules. Singer and Williams (Cell Immunol.1978: 4:1) proposed that exposure to many allogeneic HLA molecules could eventually overlap with important responses to pathogens, causing serious holes in the repertoire, some large enough to produce an acquired immunodeficiency syndrome (AIDS). The changes resulting from exposure to multiple incompatible allogeneic MHC molecules could also produce the opposite effect, an increase in a desirable immune response, or the allogeneic effect . IR-genes for histocompatible tumor resistance localized to the mouse MHC (Cancer Res. 1975;35:1586) The patient with HIV and AML, who was rendered free of both by transplantation of the right allogeneic stem cells (Blood,2010,Dec 8) supports our case. We propose that HIV is a unique and potent inducer of altered idiotype immune suppression. Explanation of the mechanism for synthetic antigens by Benacerraf (Nobel, 1980) and for viruses by Zinkernagel and Doherty (Nobel, 1986) followed from the idiotype network concept of Jerne (Nobel, 1984). Our attempt to relate these observations to the MHC and genetically controlled immune responses led us to the altered idiotype hypothesis.
Splenic FasL+CD5+ B lymphocytes are distinct from peritoneal B-1a cells and expand in response to interleukin-5 (61.2)
Authors: Lundy Steven , Alzua Brian , Reed Tamra , Klinker Matthew 
Published: January 2023

Abstract
A murine splenic B cell subset expresses the death-inducing molecule Fas ligand (FasL) and induces apoptosis of CD4+ T lymphocytes. The current study sought to further characterize FasL+ B cells and identify factors that control their growth. By flow cytometry, gating on FasL+ cells in the spleens of naïve mice demonstrated that &gt;70% of constitutively FasL+ splenocytes were CD5+/CD1dhigh B cells. In naïve mice, splenocytes with a surface phenotype of CD19+/B220+/CD5+/CD11bneg/IgMhigh/CD1dhigh showed a higher expression of FasL than any other splenic cell population. Gene array analysis comparing sorted naïve CD5+ and CD5neg splenic CD1dhigh B cells indicated some significant differences in gene expression patterns including a 3.4 fold higher expression of IL-5Rα mRNA in CD5+/CD1dhigh B cells. Addition of recombinant IL-5 to CD40L-stimulated splenic B cell cultures resulted in the selective survival and proliferation of FasL+/IgM+/CD5+ killer B cells. In Xid mice, which have severely reduced numbers of peritoneal CD5+ B cells, we found no deficiency in splenic killer B cells, suggesting that killer B cells are distinct from peritoneal CD5+ B-1a cells. Splenic CD5+ B cells from Xid mice showed higher levels of surface FasL expression than all other splenic cell populations. Together, these data demonstrate that splenic killer B cells have a distinct surface phenotype compared to other B cells, proliferate in response to IL-5, and are present in B-1a cell deficient mice.
Class switch recombination appears to be regulated by BCR/idiotype-specific T cell action (62.10)
Authors: Lemke Hilmar , Hecht Oliver , Zemlin Michael , Trad Ahmad , Tanasa Radu , Schroeder Harry 
Published: January 2023

Abstract
The T cell-dependent processes of class switch recombination (CSR) and immune maturation are believed to be driven by affinity-dependent clonal selection. However, analysis of the anti-hapten 2-phenyloxazolone response reveals that (i) thymus-dependent IgM are as heterogene-ous as natural and thymus-independent antibodies, (ii) many IgM exhibit similar or greater affinities than the classic Ox1 clonotype that (iii) dominates only after CSR, (iv) CSR selects B cell clones with shorter and more uniform CDR-H3 lengths and (v) primary IgM encoded by VH1 family genes were almost completely eliminated from the repertoire by CSR. Thus, contrary to the current paradigm, CSR appears to be clonally regulated more on the basis of BCR-specific, e.g. CDR-H3 idiotope-related, T cell action than affinity-dependent clonal selection.
Estrogen receptors bind to and activate the promoter of the HoxC4 gene to potentiate HoxC4-mediated AID induction, immunoglobulin class-switch DNA recombination and somatic hypermutation (62.8)
Authors: Mai Thach , Zan Hong , Zhang Jinsong , Hawkins J. Seth , Xu Zhenming , Casali Paolo 
Published: January 2023

Abstract
Estrogen enhances antibody and autoantibody responses through yet to be defined mechanisms. It has been suggested that estrogen upregulates the expression of activation-induced cytosine deaminase (AID), which is critical for antibody class switch DNA recombination (CSR) and somatic hypermutation (SHM), through direct activation of this gene. AID, as we have shown, is induced by the HoxC4 homeodomain transcription factor, which binds to a conserved HoxC4/Oct site in the AICDA/Aicda promoter. Here we show that estrogen-estrogen receptor (ER) complexes do not directly activate the AID promoter in B cells undergoing CSR. Rather, they bind to three evolutionary conserved and cooperative estrogen response elements (EREs) we identified in the HoxC4 gene promoter. By binding to these EREs, ERs synergized with CD154 or lipopolysaccharide (LPS) and IL-4-signaling to upregulate HoxC4 expression, thereby inducing AID and CSR, without affecting B cell proliferation or plasmacytoid differentiation. Estrogen administration in vivo significantly potentiated CSR and SHM in the specific antibody response to NP-CGG. Ablation of HoxC4 (HoxC4-/-) abrogated the estrogen-mediated enhancement of AID gene expression, and decreased CSR and SHM. Thus, estrogen enhances AID expression by activating the HoxC4 gene promoter and inducing the critical AID gene activator HoxC4.
Visualizing the requirement for homotypic T cell synapses in enhancing CD8+ T cell differentiation. (63.11)
Authors: Gerard Audrey , Omar Khan , Krummel Matthew 
Published: January 2023

Abstract
CD8+ T cells are functionally heterogeneous and mediate their effects through a variety of mechanisms. Effective adaptive immunity relies on the capacity of lymphocytes to differentiate and yet, as a cohort to respond as a single integrated entity. But the mechanism by which the “coordinated diversification” of CD8+ T cells is regulated is not fully understood. Here, we show that homotypic clustering of nascent effector cells facilitates and coordinates their differentiation. The dynamic nature of T cell clustering upon immunization was characterized by live 2-photon imaging of explanted lymph nodes. T-T interactions are highly dynamics and are driven by LFA-1 dependent interactions. These clusters are initiated by T cell activation and occur up to two days after immunization. Functionally, reducing T cell clustering inhibits the establishment of effector and memory functions. Surprisingly, after initial activation, CD8 differentiation does not require an ongoing contact with an APC, but does require T-T interactions. T cells exchange information through synaptic structures, where increased cytokine delivery and signaling is found and is required for T cells to influence each other’s fate. Altogether, we provide evidences that a ‘collective’ CD8 response is generated through direct cell-cell communication just after their elicitation. This data may explain how tolerance is maintained and how T cell responses may rapidly amplify as additional precursors are recruited.