bluuebunny/crossref_metadata_2025_split huggingface dataset:
Separation of RORgammat function in Thymocyte development and Th17 differentiation
Authors: Sun Zuoming , He Zhiheng , Ma Jian 
Published: January 2023

Abstract
RORgt regulates Th17 differentiation, thymic T cell development, and lymph node genesis. Although elimination of RORgt prevents Th17-mediated experimental autoimmune encephalomyelitis (EAE), it also disrupts thymocyte development, eventually leading to lethal thymic lymphoma. To specifically targeting RORgt-dependent Th17 autoimmunity, it is thus essential to distinguish between RORgt-regulated mechanisms in Th17 differentiation and thymocyte development. We identified two amino acid mutations within the hinge region of RORgt (RORgtM) that preferentially disrupted Th17 differentiation but not thymocyte development. Mice expressing RORgtM were resistant to Th17-mediated autoimmune EAE that was associated with defective Th17 differentiation, but maintained normal thymic T cell development and lymph node genesis, except for Peyer’s patches. The RORgtM mouse is thus an effective model for specifically evaluating RORgt-dependent Th17 immunity. We further showed that RORgtM ubiquitination at lysine 69 (K69) was greatly reduced. Mutation of wild-type RORgt K69 to arginine to prevent ubiquitination preferentially impaired Th17 differentiation but not T cell development, similar to RORgtM. Therefore, our study distinguished between important RORgt-regulated functions via a critical ubiquitination event. This study will inform the development of RORgt-based treatments that selectively target Th17-mediated autoimmunity without interrupting the development of T cells and peripheral lymphoid organs.
Prenatal exposure to cadmium alters the transciptome of regulatory T cells in C57BL/6 mice and may contribute to immunological health of the offspring
Authors: McCall Jamie L. , Elliot Meenal , Nowak Evan , Damron F. Heath , Barnett John B. 
Published: January 2023

Abstract
Cadmium (Cd) is a carcinogen present at superfund sites, in battery manufacturing facilities, in and around zinc smelters, and in cigarettes (the most common exposure pathway). In humans, prenatal Cd exposure (preCd) is associated with differential DNA methylation patterns in blood leukocytes of mother-baby pairs. C57BL/6 mice chronically exposed to low doses of Cd in utero develop abnormal immune phenotypes including reduced regulatory T cell (Treg) numbers in the spleen, but not thymus, of adult animals. These data suggest that the probable immune consequences of preCd exposure are cause for alarm. To further define the mechanisms behind these phenotypic differences, we isolated Treg and CD4+ T conventional (Tconv) cells from the spleens of preCd offspring at 8 woa. Target cells were enriched using magnetic isolation prior to purification by flow cytometry. RNA-seq and Ingenuity Pathway analyses were conducted to define the Treg and Tconv transcriptomes and identify mechanisms dysregulated with preCd exposure. Treg cells exhibited more changes in gene expression than Tconv cells. In the splenic Tregs, there were 289 significantly changed genes (166 upregulated and 135 downregulated) in females and 135 (82 upregulated and 53 downregulated) in males. Of note, only 23 upregulated genes and 3 downregulated genes were shared between females and males. However, common pathways, including CREB1 signaling, were disrupted in both sexes. As CREB signaling plays an important role in TGFβ-mediated generation and maintenance of FoxP3 Tregs, inhibition of this pathway may promote Treg instability and contribute to the decrease in Treg numbers observed in the periphery of preCd-exposed mice.
AP-1 transcription factor remodels chromatin during T cell activation.
Authors: Barski Artem , Yukawa Masashi , Jagannathan Sajjeev , Kartashov Andrey , Chen Xiaoting , Weirauch Mathew 
Published: January 2023

Abstract
Upon encountering an antigen, naïve T helper cells activate, differentiate into several lineages and contribute to immune response. Epigenetic changes at cytokine and other effector genes during activation have been described, but the underlying mechanism is not understood. We profiled open chromatin during human T cell activation using ATAC-Seq and identified regions of epigenetic changes genome-wide. Open chromatin correlated with expression at nearby genes, which were enriched for functions related to T cell activation and immune response. As AP-1 and NFAT motifs were enriched in these newly open chromatin regions, we profiled their binding using ChIP-Seq. AP-1 was present at the majority of activation-specific open chromatin regions, which were often co-bound by both transcription factors. Notably, super enhancer formation was associated with AP-1 binding and chromatin opening during T cell activation. We also found that autoimmune disease-associated SNPs were significantly enriched in the newly open chromatin regions. Our data suggest that AP-1 activity contributes to the formation of the activated T cell epigenome and that mutations at the activation-specific open chromatin regions may contribute to autoimmune diseases.
GPR65, a critical regulator of Th17 cell pathogenicity, is regulated by the CRTC2/CREB pathway
Authors: Hernandez Jeniffer B. 
Published: January 2023

Abstract
The CREB/CRTC2 pathway has emerged as an important regulator of immune function. We have previously shown that the CREB/CRTC2 pathway modulates autoimmune disease by promoting differentiation of the pro-inflammatory T cell, Th17. Although Th17 cells protect us against specific pathogens, Th17 cells have been found to cause destruction of tissue in patients with autoimmune diseases. Using RNAseq analysis, we have identified several genes that may be regulated by CREB in Th17 cells. Of these potential CREB targets, the G protein coupled receptor 65 is uniquely expressed in Th17 cells and mice deficient in GPR65 are resistant to autoimmunity. In our study, we confirm our RNAseq analysis by quantitative QPCR and chromatin immunoprecipitation. In addition, mice deficient in CRTC2, a CREB co-activator, have decreased expression of GPR65 in Th17 cells, indicating a role for not only CREB in regulating GPR65 expression, but also for CRTC2. Using a GPR65 agonist, we see an increase in GPR65 expression and Th17 cell differentiation. Therefore, blockade of GPR65 may lead to inhibition of pathogenic Th17 cells while simultaneously leaving non-pathogenic Th17 cells untouched, protecting patients against opportunistic infection.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) attenuates inflammatory response to pertussis toxin by induction of Tregs and immunosuppressive cytokine production via microRNA modulation
Authors: Al-Ghezi Zinah Zamil , Mehrpouya-Bahrami Pegah , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a halogenated aromatic hydrocarbon, is one of the most toxic compounds known and a wide-spread and persistent environmental contaminant. This chemical is a well-known contaminant in Agent Orange, a herbicide used in the Vietnam War. TCDD was released into the environment in the Seveso disaster. It is usually present in a complex mixture of dioxin-like compounds and is a carcinogen. TCDD has also been shown to act as a potent immune suppressor. In this study, we investigated the effects of TCDD on immune status by examining the splenocytes from mice following i.p. injection with pertussis toxin (PTX). We assessed cytokine levels and Treg numbers in control (PTX+Vehicle) and treated mice (PTX+TCDD). We found that TCDD-treated mice had increased levels of IL-10, while IL-6 decreased. In addition, mice treated with TCDD showed overall decreased levels of CD4+T cells and pro-inflammatory cytokines, IL-17 and IL-6. However, increases in the levels of Tregs (FoxP3+ CD4+T cells) and anti-inflammatory cytokine, IL-10 were observed in TCDD-treated mice. MicroRNA microarray analysis revealed altered miRNA profile in splenic CD4+ T cells following TCDD treatment of mice injected with PTX when compared to controls. Further evidence indicated that TCDD treatment significantly down-regulated several miRNAs such as miR101b, miR141-3p and miR-142-3p in splenic CD4+ T cells that target immunosuppressive cytokine (IL-10 and TGF-β) and transcription factor (FoxP3) genes. Collectively, these results demonstrate that TCDD suppresses the immune response after administration of PTX through modulating miRNA targeting key immune response genes involved in cytokine production and Treg differentiation.
T cell intrinsic IL-1R signaling licenses effector cytokine production by memory CD4 T cells
Authors: Jain Aakanksha , Song Ran , Wakeland Edward K. , Pasare Chandrashekhar 
Published: January 2023

Abstract
Innate cytokines are critical drivers of priming and differentiation of naïve CD4 T cells but their role in memory T cell function is largely undefined. We discovered that while TCR and CD28 ligation are primary requirements for memory T cell reactivation, IL-1 acts as a licensing signal to permit effector cytokine production by pre-committed Th1 (IFNg), Th2 (IL-13, IL-4 and IL-5) and Th17 (IL-17A, IL-17F and IL-22) lineage cells. This licensing function of IL-1 is conserved across effector CD4 T cells generated by diverse pathogenic insults and different routes of infections. We found that Il1r−/− CD4 T cells from spleen as well as small intestine can differentiate in vivo into Th1, Th2 and Th17 lineages at the steady state. However, the same CD4 T cells are unable to secrete effector cytokines following TCR ligation. Our data demonstrates that successful lineage commitment does not translate into productive effector function in the absence of IL-1R signaling. Acute abrogation of IL-1R signaling in vivo also resulted in reduced in situ IL-17A production by primed intestinal Th17 cells. Consistently, reactivation of circulating memory CD4 T cells from healthy human donors with autologous DCs in the presence of hIL-1R antagonist (Anakinra) resulted in significantly diminished IL-17A production. Mechanistically, abrogation of IL-1R signaling during reactivation led to rapid decay of T cell cytokine transcripts. Conversely, the presence of recombinant IL-1b during T cell reactivation rescued destabilized cytokine transcripts in a p38 dependent fashion. Together, these results uncover a novel layer of regulation of memory CD4 T cells and establish a broadly conserved role for IL-1 in memory CD4 T cell effector function.
A novel double edged sword in T cell development and function: Receptor-Interacting Protein Kinase 1 (RIPK1)
Authors: Thiault Nicolas , Chen Angeline , Verstichel Greet , Huysentruyt Jelle , Vandenabeele Peter , Cheroutre Hilde 
Published: January 2023

Abstract
Ripk1 is a key regulator of survival and death. This dual function is controlled by post-translational modifications: ubiquitination of RIPK1 leads to activation and survival whereas its deubiquitination or phosphorylation triggers death. In addition to its involvement in downstream signaling by many death receptors RIPK1 also functions in TCR-induced signaling cascades that either lead to activation-induced death or survival and NFkb activation. The role of Ripk1 in T cells development and functions are still poorly understood mainly because of the perinatal lethality of Ripk1 genomic deletion. To circumvent this problem, we generated T cell specific conditional KO mice by crossed Ripk1fl/fl mice with CD4-Cre. This deletion during development greatly affected the generation of TCRab thymocytes and in particular the agonist selected T cell subsets, including the NKT cells and the TCRab DN T cells. Similarly, TCRab T cells in the periphery were greatly reduced, in particular the NK T cell and DN subsets, whereas as expected TCRgd T cells were not affected. Most remaining TCRab T cells displayed a CD44+ activated phenotype and differentiation to cytotoxic cells, including the CD4 T cells. A similar effect was seen among the mucosal T cells in the gut, where few DN T cells were present and most of the intraepithelial TCRab T cells were cytotoxic CD8 T cells with high levels of Granzyme expression. All CD4 IETs were negative for ThPOK and expressed granzyme similar to their CD8 counterparts.
These observations highlight an important role for RIPK1 in thymic development of agonist selected T cells as well as conventional CD4 and CD8 thymocytes and in the periphery for the functional maturation and survival of lymphoid and tissue resident T cell subsets
Normoxic to hypoxic switch of pre-activated NK cells leads to robust proliferation and enhanced effector function via stabilization of HIF-1α and inhibition of apoptosis
Authors: Kim Jungwon , Lim Seon Ah , Moon Yunwon , Shin Min Hwa , Cassian Yee , Park Hyungsung , Lee Kyung-Mi 
Published: January 2023

Abstract
Although mature NK cells can function within hypoxic lymphatics and tissues, they show impaired anti-tumor functions in ex-vivo hypoxic environments. This raises a question regarding additional cues that may exist to allow full NK cell activation within the hypoxic tumor microenvironment. Here, we provide evidence that pre-activation of NK cells prior to hypoxic exposure is key to overcoming hypoxia-mediated impairment and inducing greater NK cell proliferation with enhanced cytolytic activity. Specifically, exposing pre-activated NK cells to 1.5% of pO2 hypoxia following 7-9 days of normoxic culture allowed HIF-1α stabilization and its target gene expression, leading to specific upregulation of NKp44 activating receptor and increased STAT3 phosphorylation. These hypoxia-exposed NK cells demonstrate concomitant reduction of apoptotic and p21/p53 senescence pathways, resulting in greater cell numbers in culture. Therefore, pre-existing proliferative signals allows HIF-1α-mediated adaptation of NK cells toward highly proliferative and cytolytic phenotypes, which may occur in vivo throughout tumor immunosurveillance.
The NF-kappa B regulator Bcl-3 controls T cell differentiation during challenge with the lymphocytic choriomeningitis virus
Authors: Jaiswal Hemant , Siebenlist Ulrich 
Published: January 2023

Abstract
Bcl-3 is an atypical member of the IκB family. Unlike classical IκBs, Bcl-3 is not degraded in response to activation signals, but instead its expression is often induced and it acts in the nucleus to modulate transcription of NF-κB target genes by associating with p50/NF-κB1 and p52/NF-κB2 homodimers. The latter complexes do not trans-activate by themselves, and association with Bcl-3 may promote or inhibit transcription in a highly gene- and context-dependent manner. Bcl-3 has profound biologic roles. Bcl-3−/− mice exhibit notably impaired adaptive and innate immune responses. Previously, we have shown that Bcl-3 regulates plasticity and pathogenicity of autoimmune CD4 T cells in the T cell transfer-induced colitis model as well as in EAE. However, it is not understood whether and how Bcl-3 may intrinsically regulate differentiation and functional responses of T cells during pathogenic challenges. To investigate for roles of Bcl-3 in primary and secondary responses to a viral pathogen, mice lacking Bcl-3 specifically in T cells (Bcl-3 ΔT) were challenged with acute lymphocytic choriomeningitis virus (LCMV) infection. LCMV antigen-specific CD8 T cell recall responses were notably deficient in Bcl-3 ΔT mice, despite comparable primary CD8 T cell antiviral responses at day 8 post infection. Bcl-3 ΔT mice instead exhibited significantly reduced proportions of LCMV-specific CD8 T cells later, by 6 weeks post infection, with remarkably fewer cells exhibiting TCM phenotypic markers (e.g. CD62L and IL-7Rα). This suggests a crucial role of Bcl-3 in long-term maintenance of antigen-specific CD8 T cells. We will present initial investigations into mechanisms by which Bcl-3 may promote antiviral T cell memory formation.
CD99 facilitates rearrangement of actin cytoskeleton during T cell activation.
Authors: Nam Giri , Choi Eun Young 
Published: January 2023

Abstract
CD99 is an O-glycosylated transmembrane protein expressed on most hematopoietic cells and has been known to play roles in transendothelial migration of leukocytes. Several reports showed that blocking CD99 on T cells rendered the cells unable to infiltrate into inflamed tissue sites. To understand how CD99 affects T cell migration, we examined the dynamics of antigen-specific T cells in the presence or absence of CD99 during allo-response. When we adoptively transferred WT or CD99-deficient T cell into B6 mice followed by intraperitoneal immunization of splenocytes from allogeneic mice, CD99-deficient antigen-specific T cells were rarely detected in the peritoneum, the antigen-existing target site, relative to WT T cells on day 3 post-immunization, consistent with previous studies. Unexpectedly, however, CD99-deficient antigen-specific T cells were detected in the peritoneum with comparable numbers to WT antigen-specific T cells at later time point, day 7. This delayed migration in CD99-deficient T cells was caused by slower activation than CD99-sufficient T cells in the spleen. We also found that actin dynamics and microcluster movement were impaired in CD99-deficient T cells during synapse formation, and these defects were due to insufficient Rac1 activation in the absence of CD99. Thus, these results demonstrate that CD99 is an important mediator of actin cytoskeleton rearrangement for adequate T cell activation and migration.
Enhancing student knowledge and understanding of Immunology using integration of a clinically relevant Immunological condition within postgraduate clinical sciences education
Authors: Sika-Paotonu Dianne 
Published: January 2023

Abstract
Proper delivery of Immunology education is fundamental for obtaining detailed understanding of important cellular processes and mechanisms. The inclusion of undergraduate Immunology teaching content within nursing, midwifery and health related courses however may vary. To support effective teaching and learning at postgraduate level for these students undertaking postgraduate clinical sciences with mixed levels of Immunology education, integration of clinically relevant Immunological course elements and related research teaching examples are needed. The purpose of this work was to successfully incorporate a clinically relevant Immunological example into Immunological course teaching. Acute rheumatic fever (ARF) is an autoimmune condition caused by untreated group A streptococcal (GAS) infection of the upper respiratory tract (and possibly skin). Multiple or severe attacks of ARF can cause permanent cardiac damage known as rheumatic heart disease (RHD). Rates of ARF in New Zealand and Australia are among the highest in the world, particularly amongst Māori and Pacific and Indigenous Aboriginal children. ARF as an autoimmune condition was used as a clinically relevant example to support improved understanding of Immunological course teaching elements. Students demonstrated improved confidence and understanding and memory recall of Immunological concepts in addition to improved in-class engagement and ability to answer questions. These observations suggest that the incorporation of a clinically relevant Immunological teaching example supported postgraduate students in their application of scientific content information and facilitated the in-depth understanding of Immunology within the clinical context.
The incorporation of Self-Directed Learning for English Second Language learners within postgraduate Clinical Health Sciences Immunology education
Authors: Sika-Paotonu Dianne , Tait Carolyn 
Published: January 2023

Abstract
The understanding of Immunological processes and mechanisms within postgraduate Clinical Health Sciences education is essential, particularly when considering pathological disease pathways. Ensuring proper learning is achieved by all students is of the utmost importance for teachers especially when considering English as Second Language (ESL) learners. Contemporary learning and teaching methods are becoming increasingly focused on student centered practices such as Self-Directed Learning (SDL) where a student determines their own learning aims and undertakes methods of their own choosing to achieve and assess their learning outcomes. To support effective learning using SDL, it is necessary students are familiar with SDL strategies. The purpose of this work was to support the adoption of SDL strategies by Nursing, Midwifery and Health ESL learners undertaking postgraduate Clinical Health Sciences Immunology education and identify their impact. Face-to-face Immunology teaching sessions for a postgraduate Pathophysiology course were delivered with the inclusion of SDL strategies to support and facilitate effective learning. These strategies were carefully presented to ensure communication was culturally appropriate for all, especially ESL learners. Positive in-class feedback regarding SDL strategy content was received from all students in addition to favorable formal evaluation comments and student satisfaction scores for the Immunology course content. Student assessment outcomes for ESL learners were encouraging. These finding support the incorporation of SDL learning strategies delivered to ensure cultural appropriateness and support effective learning for postgraduate Immunology education.
Knowledge translation for Cancer Immunotherapy and Immunology that is culturally appropriate and relevant within a Pacific context
Authors: Sika-Paotonu Dianne , Laban Luamanuvao Winnie 
Published: January 2023

Abstract
Pacific peoples living in New Zealand and in the Pacific region remain disproportionately affected by some cancers and have less favourable outcomes when compared with non-Pacific populations. Researchers stand to benefit from research efforts that work collectively and in partnership with Pacific communities. Biomedical research efforts to engage and dialogue with Pacific communities in New Zealand have been limited. The purpose of this work was to support the appropriate delivery and knowledge translation of Cancer Immunotherapy and associated Immunological concepts of direct relevance and importance to Pacific communities. A Pacific Fono (gathering) event was held through the local university that invited current and previous postgraduate Clinical Health Science students who were of Pacific heritage. A portion of this event was presented by a female Pacific Biomedical scientist and dedicated to supporting increased knowledge and awareness of emergent cancer immunotherapeutic based strategies for treating cancer. This event was well attended by current and previous Pacific postgraduate Clinical Health Science students of Pacific heritage many of whom are now employed as health professionals and included current and former health leaders, family members, health researchers, community representatives. Positive verbal and written feedback was received from those in attendance with a request for more regular events be held. The Pacific Fono event was the appropriate means to support knowledge translation of Immunotherapeutic strategies for treating cancer by engaging and communicating with Pacific community members in a culturally appropriate, clear and meaningful way.