bluuebunny/crossref_metadata_2025_split huggingface dataset:
Excessive miR-27 expression impairs regulatory T cell-mediated immunological tolerance
Authors: Cruz Leilani Ong , Hashemifar Somaye Sadat , Cho Sunglim , Wu Cheng-Jang , Lin Ling-Li , Nguyen Duc T. , Khan Aly Azeem , Lu Li-Fan 
Published: January 2023

Abstract
MicroRNAs (miRNAs) are tightly regulated in the immune system as aberrant expression of miRNAs often results in hematopoietic malignancies and autoimmune diseases. Previously, elevated levels of miR-27 in T cells isolated from multiple sclerosis patients has been suggested to facilitate disease progression through inhibiting Th2 immunity and promoting pathogenic Th1 responses. Here we show while mice with T cell-specific overexpression of miR-27 harbor dysregulated Th1 responses and develop autoimmune pathology, these disease phenotypes are not driven by miR-27 in effector T cells in a cell autonomous manner but rather resulted from a perturbed regulatory T (Treg) cell compartment. Excessive miR-27 expression in T cells severely impairs thymic Treg cell development and TGFb-mediated conversion of peripheral Treg cells from conventional T (Tconv) cells. Moreover, Treg cells with exaggerated miR-27-mediated gene regulation exhibit diminished homeostatic potential and suppressor function in vivo. Mechanistically, miR-27 represses a subset of genes that play critical roles in controlling multiple aspects of Treg cell biology. Collectively, our data show miR-27 functions as a key regulator in Treg cell development and function and suggest that proper regulation of miR-27 is pivotal to safeguard Treg cell-mediated immunological tolerance.
Long noncoding RNA MEG3-4 regulates IL-1β during pulmonary bacterial infection by repressing microRNA-138
Authors: Li Rongpeng , Wu Min 
Published: January 2023

Abstract
Long noncoding RNAs (lncRNAs) modulate various biological processes; however, their function in host immunity response against infection is largely unknown. Here, we identify an intergenic lncRNA MEG3 (linc-MEG3) as a tissue specific regulator for pulmonary immunity during Gram-negative bacterial infection. Among the 10 transcripts of linc-MEG3, transcripts 1 and 4 are main regulators as being discovered the most downregulated in mouse lungs after bacterial infection. Overexpression of linc-MEG3-4 in mice led to intensified inflammatory response, severe lung injury, systemic dissemination and ultimately increased mortality. Alveolar epithelial cells and alveolar macrophages (AM) were major cell populations that are targeted by linc-MEG3-4. Due to its 3′ sequences complementary to microRNA-138 (miR-138), linc-MEG3-4 competitively binds miR-138 and thereby freeing its target IL-1β mRNA to intensify inflammatory responses. Our results characterize linc-MEG3 as a novel pulmonary inflammatory regulator of bacterial infection through a miR-138/IL-1β/NF-κB axis.
VprBP, an HIV target protein, is vital for immune responses by controlling T cell growth, proliferation and senescence.
Authors: Wan Yisong , Guo Zengli 
Published: January 2023

Abstract
Naïve mature T cells are maintained in a quiescent state with a low rate of cell size growth (biomass increase due to enhanced metabolism and biosynthesis) and proliferation. Disturbances inflicted by infection and inflammation, often trigger cells to exit quiescence and enter cell cycle, followed by rapid proliferation to restore homeostasis. Cell size growth is imperative for proliferating cells to compensate for the halving of cellular constituents for each division. Thus, proper coordination of cell growth and cell cycle entry of T cells is essential to mount effective immune response. Nonetheless, little is known about how cell cycle entry is controlled and even less about how cell size growth is regulated in T cells.
We studied protein expression during T cell growth and cell cycle entry using quantitative proteomic approach. VprBP, an HIV target protein, was identified to be one of the highly upregulated factors. We found that VprBP was required for the cell growth and cell cycle entry of activated T cells. VprBP deletion abrogated T cell expansion during antiviral and autoimmune responses in vivo. VprBP-deficient cells drastically stabilized p53 protein with elevated expression of p53 target genes. Intriguingly, we found that although p53 deletion failed to correct the T cell growth defect due to VprBP deletion, it largely restored the cell cycle entry of VprBP-deficient T cells. In addition, VprBP deletion led to a premature senescence phenotype in T cells associating with increased cellular aging markers. These results suggest that VprBP controls T cell growth, cell cycle entry and senescence via discrete molecular programs. The recent findings and the underlying mechanisms will be discussed in detail in this presentation.
Molecular mechanisms required for TCR-mediated formation of TCR-CXCR4 heterodimers
Authors: Dinkel Brittney A , Kremer Kimberly , Osborne Douglas Grant , Reed Brendan Kearney , Schrum Adam G , Hedin Karen E 
Published: January 2023

Abstract
T cell immune activation is frequently cross-regulated by CXCR4, which regulates T cell migration through binding its ligand SDF-1 (CXCL12). Here, we define a novel molecular mechanism by which CXCR4 directly impacts T cell immune function even in the absence of SDF-1. Our lab recently reported that, even in the absence of SDF-1, T cell receptor (TCR) stimulation causes CXCR4 to physically associate with the TCR and form a TCR-CXCR4 heterodimer. Moreover, blocking formation of TCR-CXCR4, with the CXCR4 antagonist AMD3100 or by CXCR4 siRNAs, selectively impairs TCR-stimulated signaling, inhibiting T cell production of IL-2, IL-4, IL-10, and TNF but not IFN-λ. Here, we investigate the molecular mechanisms required for TCR-induced TCR-CXCR4 formation in the absence of SDF-1. Using fluorescence resonance energy transfer (FRET) to detect TCR-CXCR4, we discovered important roles for specific TCR-induced kinases and also particular CXCR4 structural motifs, leading us to propose that a kinase-driven receptor trafficking mechanism is responsible for formation of TCR-CXCR4 heterodimers in response to TCR ligation. Furthermore, we have identified CXCR4 structural motifs and an E3 ligase that act as negative regulators of TCR-CXCR4 heterodimer formation. Thus, TCR ligation triggers formation of TCR-CXCR4 complexes that mediate T cell functions. Targeting formation of TCR-CXCR4 complexes may be a novel approach to modulate T cell-mediated immunity.
Environmental cues in Casp8-deficient mice enhance virus-specific T cell expansion and terminal differentiation
Authors: Feng Yanjun , Daley-Bauer Lisa , Roback Linda , Mocarski Edward 
Published: January 2023

Abstract
Cell autonomous death is balanced against survival signaling to establish T cell levels in the course of primary as well as secondary responses to infection. It is known that mitochondrial (intrinsic) cell death contributes to T cell contraction; however, the question remains about the role of extrinsic cell death in the T cell response. Caspase8 (Casp8) initiates apoptosis downstream of death receptor activation while also suppresses RIP3-mediated necroptosis. We have employed wild type (WT), Rip3−/− and Casp8−/− Rip3−/− (DKO) mice to address the contribution of Casp8-dependent apoptosis as well as RIP3-dependent necroptosis in the antiviral T cell response. Although both Casp8 and RIP3 are dispensable for the T cell response to murine cytomegalovirus (MCMV) infection, we found that DKO mice exhibit differences in T cell characteristics compared to WT or RIP3-deficient mice. Interestingly, the T cell populations in naïve DKO mice show increased activation markers (CD44LhiKLRG1hiCD127lo). This pre-activated status results in more abundant virus-specific effector T cells in DKO mice following expansion at 7 dpi. Importantly, DKO T cells respond the same as WT T cells when adoptively transferred into WT environment; however, adoptive transfer of DKO splenocytes into WT recipients results in greater expansion and terminal differentiation of the recipient (WT) T cell population during infection. Altogether, even though Casp8 and RIP3 are dispensable for T cell expansion and contraction when examined directly, Casp8-dependent environmental cues influence T cell expansion during infection and even drive WT T cells to behave like Casp8-deficient T cells when present together during virus infection.
Signaling through PD-1 on CD8 T cells is critical for antigen-independent maintenance of immune memory
Authors: Yuzefpolskiy Yevgeniy , Baumann Florian Martin , Penny Laura Anne , Kalia Vandana , Sarkar Surojit 
Published: January 2023

Abstract
PD-1 is highly expressed on CD8 T cells during activation, both in acute and chronic viral infections. Inhibitory signaling in cytotoxic T cells through the PD-1 axis is well characterized during chronic infections and has led to the development of potent blockade therapies that restore function to otherwise exhausted CD8 T cells. However, the functional significance of transiently increased PD-1 expression on CD8 T cells early after activation and its rapid down-regulation following clearance of antigen during acute infections, remains to be characterized. The enigma is – expression of PD-1 (an immunological brake) during activation temporally coincides with rapid proliferation and production of copious amounts of signature effector cytokines (IFN-γ and TNF-α). We generated PD-1−/− antigen-specific CD8 T cells to study its cell-intrinsic role during acute infection with LCMV. Unexpectedly, PD-1−/− cells did not exhibit increased proliferation early during infection, or enhanced accumulation at the peak of expansion. PD-1−/− CD8 T cells were also unaltered in their polyfunctionality and granzyme B expression. Despite robust effector properties, PD-1−/− CD8 T cells underwent precipitous contraction, leading to near ablation of the memory pool. Mechanistically, in vivo analysis of PD-1−/− memory cells showed a severe defect in antigen-independent homeostatic proliferation due to decreased sensitivity to IL-2, −7, and −15 signals, without evident change in the expression of common gamma-chain cytokine receptors. These studies demonstrate a previously unrecognized role of PD-1 signaling in programming of memory CD8 T cell maintenance and could make it a novel target for manipulating vaccine-induced memory T cell longevity.
Integrating Group-Learning for First-Year Pharmacy Immunology Course to Enhance Students Understanding and Comprehension
Authors: Bowar Benjamin Charles , Royan Ayla , Shellip Alla , Fazal Nadeem , Fazal Nadeem 
Published: January 2023

Abstract
This research hypothesizes that integrating group-learning oriented multiple-choice study guides for first-year pharmacy immunology course will enhance students learning, understanding and comprehension of complicated material. Immunology questions (300 MCQs) were selected based on the criteria of lectures topics, difficulty level and meeting the specific objectives for every lecture that was presented to students and covered in this exam. Study guide was uploaded to Moodle three weeks before the examination and students were given a free access to it with the ability to download and print it. The survey was taken at the end of examination to assess the benefit of study guide to students. Likert-type Ordinary Scale data analysis was used to determine if hypothesis was supported and study endpoints were met. Primary endpoint was to determine the effectiveness of utilizing the study guide in student learning. Secondary endpoint was to determine if students prefer to study in learning groups and what resources were most commonly utilized to find answers to questions. Our studies found that the majority of the students 69% indicated study guide was very beneficial to them and helped to make their study more focused and practicing questions helped them to understand complicated immunology concepts better. Moreover, 65% of the students agreed or strongly agreed that study guide helped them not only to prepare to examination but also to improve the overall exam score. In conclusion, the results of this study suggest that group-based learning approach utilizing a multiple-choice study guide was very beneficial to a first-year pharmacy immunology course and positively supplemented materials being covered in a classroom lecture setting.
Mentoring Undergraduates: Challenges and Choices in a Unique Experience in Entrepreneurship
Authors: Liepkalns Justine S 
Published: January 2023

Abstract
Undergraduate research has the benefit of helping students make a transition from passive learning to active learning; however, students new to research are presented with a catch-22 when trying to identify a research laboratory to work in. I present a case study of a unique mentoring experience and what I have been learning about mentoring writ large. Among issues faced included fostering independent thinking and enthusiasm, attribution of credit, calibrating mentor involvement, establishing “protected time” and regular meetings, and building a relationship while still maintaining authority. This case includes an added layer of complexity: entrepreneurship. Two freshmen and I began an online public fundraising campaign for a small laboratory project involving a screening method for Ebola. This allowed me, as a post doctoral fellow, to start a lab project within a different discipline with lab space provided by a supportive biology department. The resulting screening method was filed for a preliminary patent at the United States Patent and Trademark Office. The students had experience in giving an oral presentation at a conference and participating in local outreach during a local science fair. We were awarded a booth at the Atlanta Science Festival. One of the students has received additional funding and gave an invited TEDx talk; the other wrote an essay published in a peer-reviewed journal. Starting this project through unconventional means and maintaining a trusting mentoring relationship was important in shaping a platform from which to propel these students’ careers forward.
Immunology education within a Postgraduate Nursing Science program in New Zealand
Authors: Sika-Paotonu Dianne 
Published: January 2023

Abstract
Immunology is key to understanding the cellular basis for certain diseases. Postgraduate Nursing Science students with a limited undergraduate background in Biomedical Science may find Immunological course components challenging. The goal was to successfully incorporate and establish a substantial Immunological component within the postgraduate Pathophysiology course for Nursing Science and Health students at Victoria University of Wellington in New Zealand. In-class teaching sessions were conducted that covered the fundamental concepts of Immunology and included Innate, Adaptive Immunity, Inflammation and Immunopathophysiology lessons. A variety of teaching and learning approaches and strategies were employed to facilitate in-class learning for students and support understanding, and improve participation and student engagement with in-class activities. These included the use of Youtube video clips, animations depicting key cellular and mechanistic interactions, one-on-one peer discussions and traditional lecture sessions interspersed with brief question and answer interactions designed to gauge understanding and also consolidate learning. Cumulative data showed favourable student outcomes were achieved for Immunological assessment components. Student satisfaction and teaching scores based on formal student evaluation processes also showed positive responses regarding the Immunology course elements. This work highlights the successful incorporation of essential Immunological components into a teaching curriculum for Postgraduate Nursing Science education in New Zealand.
The role of Type I and Type II Interferon in the adaptive response to blood stage malaria infection.
Authors: Hahn William O , Gale Michael J , Stetson Dan , Liles WC , Pepper Marion 
Published: January 2023

Abstract

Background
The adaptive immune response is critical during the host response to blood stage malaria infection but the cytokine networks important in the development of an appropriate adaptive response are unclear. Type I and Type II gene networks are upregulated in response to blood stage malaria infection in both humans and mice.

Methods
In a murine model of blood stage malaria infection (Plasmodium yoelli), we utilized a tetramer-based approach to examine the effects of Type I and Type II interferon on the antigen specific adaptive immunologic CD4+ T-cell and B-cell response. Disruptions in both Type I and Type II interferon had substantial effects on the cellular immune response and also affected the course of infection. Mice with disruption in Type I Interferon signals had worsened parasitemia early whereas mice with disruption in Type II interferon signals had problems with delayed clearance of the parasite.

Conclusion
We conclude that Type I and Type II Interferon responses have distinct roles in the host response to blood stage malaria infection. We conclude that early Type I Interferon signals are important for appropriate adaptive response whereas early Type II interferon signals are disruptive for late clearance of the parasite.
Lytic granule convergence is essential for NK cells to promote targeted killing while preventing collateral damage
Authors: HSU HSIANG-TING , Viswanath Dixita , Mace Emily , Christakou Athanasia , Wiklund Martin , Önfelt Björn , Orange Jordan 
Published: January 2023

Abstract
NK cell activation triggers serial events leading to lysis of diseased cells: 1) granule convergence, preformed lytic granules rapidly cluster to the microtubule-organizing center (MTOC), 2) granule/MTOC polarization to the immunological synapse, and 3) degranulation, exocytosis of lytic contents onto the target cell. Granule convergence requires LFA-1 signaling and dynein motor function. Yet, it remains elusive how lytic granule convergence contributes to NK cell cytotoxicity. Using Drosophila S2 cells, we regulate NK cell signal inputs to precisely control granule convergence and degranulation. In the absence of LFA-1 signaling, the average distance of lytic granules to the MTOC increased &gt;1.3 fold, indicating diffuse granule localization. Using imaging flow cytometery, we determined that without LFA-1, the synaptic accumulation and degranulation of lytic granules decreased by 3.3 and 2.5 fold, respectively suggesting undirected granule release. Using an ultrasound-guided-acoustic-trap-microscopy system to enforce live single NK cell with multiple target cell contacts, we determined killing efficiency with real-time granule tracking. NK cells activated by CD16 alone without co-engaging LFA-1 showed ~40% lower targeted killing and ~30% higher non-specific killing of neighboring unlabeled “bystander” S2 cells. Finally, we used ciliobrevin D, a dynein inhibitor, to physically block granule convergence in NK cells conjugated with physiologically relevant target cells. Dynein-inhibited NK cells caused ~36% increase in bystander killing. Thus, we demonstrated that NK cells converge lytic granules to improve the efficiency of targeted lytic granule secretion and prevent collateral damage to neighboring tissue.
A context-dependent role for IL-21 in modulating the differentiation, distribution, and abundance of effector and memory CD8 T cell subsets
Authors: Tian Yuan , Cox Maureen A , Kahan Shannon M , Ingram Jennifer T , Bakshi Rakesh K , Zajac Allan J 
Published: January 2023

Abstract
The activation of naïve CD8 T cells typically results in the formation of effector cells (TE) as well as phenotypically distinct memory cells that are retained over time. Memory CD8 T cells can be further subdivided into central memory (TCM), effector memory (TEM) and tissue-resident memory (TRM) subsets, which cooperate to confer immunological protection. Using mixed bone marrow chimeras and adoptive transfer studies in which CD8 T cells either do or do not express the IL-21 receptor (IL-21R), we discovered that under homeostatic or lymphopenic conditions IL-21 acts directly on CD8 T cells to favor the accumulation of TE/TEM populations. The inability to perceive IL-21 signals under competitive conditions also resulted in lower levels of TRM phenotype cells and reduced expression of granzyme B in the small intestine. Furthermore, IL-21 differentially promoted the expression of the chemokine receptor CX3CR1 and the integrin α4β7 on circulating CD8 T cells in the mixed bone marrow chimeras and on CD8 T cells primed in vitro. Thus, IL-21 may influence CD8 T cell migration by modulating the expression of CX3CR1 and α4β7. The requirement for IL-21 to establish CD8 TE/TEM and TRM subsets was overcome by acute lymphocytic choriomeningitis virus infection. Nevertheless, memory virus-specific CD8 T cells remained dependent on IL-21 for optimal accumulation in tissues under lymphopenic conditions. Overall, this study reveals a context-dependent role for IL-21 in sustaining effector-phenotype CD8 T cells and influencing their migratory properties, accumulation, and functions.
Liver sinusoidal endothelial cells induce the tolerogenic and regulatory feature of autoreactive CD4+ recent thymic emigrants
Authors: Ge Qing , Xu Xi , Zhang Shusong , Wang Ke 
Published: January 2023

Abstract
Mechanisms of peripheral tolerance play a critical role in preventing T cells that escape from negative selection in the thymus from initiating autoimmune reactions. We found that a fraction of CD4+ recent thymic emigrants (RTEs) were retained in the liver independent of the secondary lymphoid organs. Following transfer into RAG−/− recipients, CD4+ liver RTEs induced more severe organ-specific inflammation and cell infiltration than lymph node RTEs, indicating that more autoreactive RTEs were retained in the liver. Compared to RTEs from the lymph nodes, more CD4+ RTEs from the liver acquired activated phenotype (CD44hiCD62LloCXCR3hiPD-1loFoxp3−) with high expression of LAG3, FasL, IL-10, and IFN-γ. These liver RTEs also acquired regulatory functions as they could suppress the proliferation of naïve T cells in vitro. We further found that liver sinusoidal endothelial cells could induce the tolerogenic and regulatory phenotype of liver RTEs via cellular interaction. The expression of MHC, Aire, and Notch all contributed to RTEs’ acquisition of liver tolerance. These results suggest that the liver is the first checkpoint in the periphery to filter, retain, and enforce tolerance to autoreactive CD4+ thymic emigrants that escape from negative selection.