bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effector memory CD4 T cells engage myeloid cells through TNFR and CD40 to induce innate inflammation and autoimmune pathology independent of pattern recognition receptors
Authors: Meibers Hannah , McDaniel Margaret M , Jain Aakanksha , Chawla Amanpreet Singh , Pasare Chandrashekhar 
Published: January 2023

Abstract
T cell mediated autoimmune diseases and associated tissue pathology is commonly attributed to inflammatory cytokines produced by the innate immune system. Similarly, CAR-T cell therapy and checkpoint blockades lead to innate cytokine storms and inflammation. While blocking individual cytokines can alleviate some of this pathology, the upstream mechanisms permitting self-reactive T cells to facilitate an innate inflammatory response remain unknown. We have discovered critical players that are engaged by effector memory CD4 (Tem) T cells to induce a broad transcriptional program in cells of the innate immune system. The pro-inflammatory response induced in innate immune cells is independent of pattern recognition receptors (PRRs), but mirrors genes induced by microbial recognition. We find that the innate inflammation is driven by combined engagement of TNFR and CD40 on myeloid cells presenting cognate antigen to Tem cells. Pro-inflammatory cytokine production and autoimmune pathology can be completely rescued by ablating the CD40 and TNFR pathways in several models of T cell driven inflammation. Thus, we have discovered a previously unknown trigger of innate inflammation and autoimmune pathology and propose that targeting this signaling node could be a more effective therapeutic approach than previously characterized cytokine-specific remedies.
Supported by grant from NIH (R01 AI123176)
IRF5 regulation of CD4+ T cell metabolism controls CD40L expression
Authors: Brune Zarina , Matta Bharati , Barnes Betsy 
Published: January 2023

Abstract
Systemic Lupus Erythematosus (SLE) is a devastating autoimmune disease that results from failure of the immune system to distinguish “self” from “non-self”. Studies in our lab and others demonstrated that human SLE CD4+ T cells have elevated levels of IRF5 and increased metabolism, while Irf5 knockout murine CD4+ T cells show diminished utilization of oxidative phosphorylation and glycolysis, respectively. However, how IRF5 contributes to CD4+ T cell support of B cell function and dysfunction has not been fully elucidated. Here, using IRF5 KO C57BL/6J mice, we show that loss of IRF5 in CD4+ T cells directly contributes to defects in plasmablast generation. Examination of the CD40-CD40L interaction shows significant decreases in CD40L expression in Irf5 KO CD4+ T cells. Examination of Cd40lg transcript expression shows no difference in mRNA expression in Irf5 KO murine CD4+ T cells when compared to WT. This finding indicated a novel post-transcriptional regulatory role for IRF5. Examination of the canonical mTOR pathway, a key translational regulator, shows decreased phosphorylation of the S6 ribosomal protein upon loss of Irf5, indicating diminished activity of the mTOR pathway. mTOR inhibition with rapamycin in turn results in decreased CD40L expression, supporting a role for mTOR in CD40L regulation. As mTOR signaling is known to be regulated by cellular metabolism, we examined if loss of IRF5 results in altered T cell metabolism. We found that Irf5 KO T cells have decreased glucose metabolism and increased glutamine metabolism. This data has increased our understanding of how metabolism influences CD4+ T cell function and provided insight into novel post-translational regulatory roles for IRF5 via T cell metabolic regulation.
Enhancing lysosomal lipid metabolism prevents the loss of Kupffer cells in non-alcoholic steatohepatitis and attenuates liver pathology
Authors: Chan Mandy M , Daemen Sabine , He Li , Gainullina Anastasiia , Artyomov Maxim N , Razani Babak , Schilling Joel D 
Published: January 2023

Abstract
During the development of non-alcoholic steatohepatitis (NASH), liver resident Kupffer cells (KCs) are progressively lost and replaced by monocyte-derived macrophages (MdMs). The impact of KC loss on NASH pathology is not currently known. Given the important role of KCs in maintaining tissue homeostasis and clearing blood-borne antigens, we hypothesized that KC depletion contributes to NASH pathogenesis. Thus, we aimed to elucidate the mechanism(s) of KC loss and to devise a strategy to enhance KC survival during NASH.
We had previously shown that lipids can cause lysosomal cell death in macrophages. Using a mouse model of NASH, we discovered that KCs also develop phagolysosomal pathology. Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and lipid metabolism that has been shown to rescue lysosomal dysfunction in other metabolic diseases. To test whether TFEB activation could protect against KC death in NASH, we generated a mouse model in which a KC-specific Cre induces expression of a TFEB overexpression construct (KCTFEB). Despite having similar body and liver weight as WT mice fed a NASH-inducing diet, KCTFEB mice had a striking preservation of KC number. Moreover, KCTFEB mice had reduced recruitment of pro-inflammatory MdMs and this was associated with lower liver triglyceride and injury. RNA sequencing of KCs from transgenic and WT mice revealed that TFEB induced the expression of several lysosomal and lipid metabolic genes. Together these findings provide important proof-of-concept evidence that KC loss contributes to disease pathology in NASH and suggest that targeting macrophage lysosomal/lipid metabolic function could be a useful strategy to enhance resident macrophage survival.
Supported by grants from ADA-118IBS280, DDRCC-P30DK052574, NIH T32-AI007163, and NSF GRFP-DGE-1745038
Transcription factor profiling reveals activation of Type II Natural Killer T cell effector functions in response to Francisella tularensis infection.
Authors: Torres Cameron M 
Published: January 2023

Abstract
The bacterium Francisella tularensis (Ft) is the causative agent of human tularemia. When untreated, tularemia can reach a mortality rate as high as 30% in healthy adults with inhalation of as few as 10 colony forming units (CFU) inducing respiratory tularemia. While Ft is spread from zoonotic sources in nature, the ease of aerosol spread and high mortality in respiratory form led to its weaponization and concern for bioterrorism. Exposure to Ft elicits the cytokine storm, in which the immune system over-responds to the presence of the bacterium releasing massive amounts of proinflammatory and regulatory cytokines. Natural Killer T (NKT) cells are important immune cells that have both activating and inhibitory effector mechanisms. NKT cells are activated very early following Ft infection suggesting a critical role in the innate immune response to the bacterium. NKT cells are categorized into two distinct subsets based on their antigen recognition of CD1d-tetramers loaded with α-galactosylceramide (αGalCer-tetramer), though their individual characteristics in regulating inflammation are ill-defined. Type I NKT cells, similar to CD4+ αβ T helper cells, have been shown to express varied transcription factor (TF) profiles, e.g., T-bet, GATA3, and RORγT, contributing to either Th1, Th2 or Th17 phenotypes. It is not currently known whether this same TF profile classification exists within type II NKTs. The purpose of this research project is to investigate the activation of the type II NKT cell subset and characterize their TF profiles in response to Ft infection. This data will lead to a better understanding of the role of type II NKT cells in Francisella-mediated immunity.
Supported by National Institute of General Medical Sciences (NIGMS) Research Initiative for Scientific Enhancement (RISE) grant R25 GM 06921-18
Key contribution of NK cells to inflammation after muscle injury
Authors: Cevik Hilal , Gangadin Isabelle , Boyer Justin G , Millay Douglas , Waggoner Stephen N 
Published: January 2023

Abstract
Immune activation after tissue injury is required for removal of dead cells and debris to permit subsequent regenerative healing. Natural killer (NK) cells are innate lymphocytes that are essential for immune defense and for regulation of inflammation. NK cells limit fibrosis after cardiac muscle damage, yet the role of these cells during skeletal muscle inflammation is less clear. We hypothesize that NK cells promote acute inflammation after muscle damage but that NK cell responses must be resolved to permit regenerative healing. Following bilateral injection of cardiotoxin into tibialis anterior and gastrocnemius muscles of C57BL/6 mice, NK cell accumulation in injured muscle was detectable within 18 hours and peaked four days post-injury. Selective depletion of NK cells using a titrated dose of anti-NK1.1 antibody prior to cardiotoxin injection resulted in a substantial reduction in the overall infiltration of numerous immune cell types, including T and B cells, into the injured muscle. Thus, NK cells are an important mediator of cellular inflammation following muscle damage. Future studies will determine the mechanism by which NK cells contribute to this inflammatory response and how ablation of NK-cell mediated inflammation impacts healing of damaged muscles.
Supported by National Institute of Heath (NIH) (R01-AI148080)
The Effect of Malnutrition on T-cell Circadian Rhythms
Authors: Foster Takesha R , Dadzie Kwesi A , Adams Olivia , Gubbels-Bupp Melanie R 
Published: January 2023

Abstract
In mammals, T-cell migration is under circadian control, likely to anticipate daily rhythms in infection risk. Glucocorticoids are a major controller of circadian processes and malnutrition is associated with increased glucocorticoid secretion. Previous studies suggest malnutrition may impart a “super-quiescent” phenotype to T-cells, enabling a greater number of naïve T-cells to survive short-term malnutrition albeit with diminished function. Thus, we hypothesize that malnourished T-cells may conserve energy by disengaging from rhythmic migration under circadian control and/or foregoing migration to reside in the bone marrow instead. To test this hypothesis, the total number of nucleated cells and naïve CD4+ and CD8+ T-cells in the blood, spleen, bone marrow, and brachial and mesenteric lymph nodes were enumerated by flow cytometry every four hours over the course of one day from control and malnourished mice. Additionally, expression levels of CD127 and CXCR4 in both T-cell populations and the concentration of glucocorticoids in the blood were assessed. A better understanding of how malnutrition affects the circadian rhythm of T-cell migration will not only help identify the mechanisms of how circadian rhythms work, but also how organisms’ circadian rhythms change in response to malnutrition. This knowledge of how malnutrition disrupts the circadian rhythm of T-cells may help improve vaccination strategies in malnourished children.
Supported by NSF-MRI [DBI- 1920116] NSF -RUI [IOS-1951881]
Characterization of the cross-reactive T cell repertoire in the context of heterosubtypic influenza A virus infection
Authors: Gaevert Jessica A , Duan Susu , Thomas Paul G 
Published: January 2023

Abstract
The T cell receptor (TCR) repertoire is extremely diverse and plays an instrumental role in fighting off pathogens individuals encounter in a lifetime. A key aspect of the immune system combatting the diverse array of pathogens an individual sees may be TCR cross-reactivity, where a TCR can recognize more than one peptide displayed on an MHC-I molecule. The number of possible peptides presented to the immune system exceeds 1015, and this number is greater than the number of possible T cells the immune system can generate and sustain. Thus, a certain portion of the T cells in an immune system must be cross-reactive. Specifically, cross-reactive TCRs may play a key role in allowing the immune system to adapt to rapidly evolving pathogens, such as influenza A virus (IAV). Utilizing 8 variant influenza viruses for priming and secondary challenge, our preliminary data has shown that cross-reactive TCRs seen in primary infection with one IAV can mount a robust and effective memory response to a different IAV, across a range of mutations. However, selection for cross-reactive receptors may create a narrowed repertoire consisting of a few clonotypes over the course of many repeated heterosubtypic IAV infections, covering a narrow range of antigenic space representing the mutant epitopes encountered. Paradoxically, this selection for cross-reactivity may provide a substantial escape opportunity with future antigenic variations. Ongoing work focuses on how repeated IAV challenges shape the repertoire, and how previous infections inform future responses by selected cross-reactive T cell pools.
Supported by grants from NIH (R01 112404040) and the St. Jude Children’s Research Hospital Graduate School
A fluorescent reporter model to study the role of TDC during infection and cancer
Authors: Kuka Mirela , Fiore Alessandra , Sala Eleonora , Oberrauch Federico , Provero Paolo , Riba Michela , Cristofani Claudia , Iannacone Matteo 
Published: January 2023

Abstract
TDC are hematopoietic cells that combine dendritic cell (DC) and conventional T cell markers and functional properties. They were identified in secondary lymphoid organs (SLO) of naïve mice as cells expressing CD11c, MHC-II, and TCRβ chain. TDC expand in response to TCR-mediated stimulation, but they also express the DC lineage marker Zbtb46. Moreover, TDC are characterized by a cytotoxic gene signature, including high expression of IFNγ and granzymes. Unfortunately, using CD11c as a marker for TDC has the caveat of its upregulation on different cells (including T cells) upon activation. Therefore, a more specific marker could be useful to further investigate TDC functions in peripheral organs or during inflammation. We exploited the unique genetic profile of TDC to obtain a reporter mouse model in which TDC are marked with two different fluorescent proteins (Zbtb46-GFP and Gzmb-Tomato). This model allowed us to use Zbtb46 instead of CD11c as a marker for TDC, in order to investigate the frequency and localization of TDC in peripheral tissues such as liver, small intestine, and lung. RNA sequencing analysis confirmed that TDC identified with this reporter model have an overlapping gene signature with the one already reported for TDC. In addition, frequency and total numbers of Zbtb46+ TDC in the SLO recapitulated those previously found using CD11c, thus confirming the validity of our model. Interestingly, we found that TDC numbers in the SLO increased upon LCMV infection, indicating that TDC might play a role during viral infections. Further studies aimed at identifying the localization of TDC in peripheral organs, and their role in several pathological settings are ongoing.
M.K. is supported by the Italian Ministry of Education, University and Research grants SIR-RBSI14BAO5 and PRIN-2017ZXT5WR
Tissue- and age-specific adaptations of human γδT cells in early life
Authors: Gray Joshua I , Chin Athena , Connors Thomas J , Guyer Rebecca S , Rybkina Ksenia , Bradley Marissa C , Matsumoto Rei , Farber Donna L 
Published: January 2023

Abstract
γδT cells are unconventional T lymphocytes which seed peripheral tissues in early life. They provide frontline anti-pathogen, anti-cancer and homeostatic responses, rapidly initiated in response to signals of cellular stress independent of MHC-recognition. However, the role of γδT cells in humans has been difficult to assess given their purported tissue residency. Using tissues obtained from organ donors, we conducted flow cytometry, TCR-sequencing, and stimulation assays on γδT cells isolated from blood, spleen, lung, intestines and lymph nodes (LN) to create an ‘atlas’ across the human body throughout life. γδT cells were enriched in the blood, spleen, lung, and jejunum in early life, whereas LN proportions were maintained at low levels. Vδ1 and Vδ2 γδT cell subsets also exhibited tissue- and age-specific phenotypes: Vδ1 cells predominated in all organs in infancy except the lung. They were ‘naïve-like’, acquiring a mature phenotype with age, whereas Vδ2 possessed an effector memory signature, even in donors a few days old. Functionally, Vδ2 cells produced IFNγ, TNFα, GzmB and perforin at high levels in childhood. By contrast, Vδ1 cells favored Areg production during infancy but acquired a cytotoxic profile into adulthood. TCR analysis revealed clonal expansion in mucosal organs, whereas lymphoid sites had increased diversity in early life. Despite this site-specific clonal expansion, V-chain usage was stably distributed across organs and did not show the tissue-specific biases seen in mice. Our analyses reveal that γδT cells may play an outsized role in pediatric tissue immune responses and identify potentially divergent roles of specific subsets that contribute to tissue immunity during the most vulnerable years of life.
The functional and molecular determinants of HCV-specific CD8 T cell responses during early infection
Authors: Cai Curtis , Samir Jerome , Adikari Thiruni , Peters Tim , Luciani Fabio 
Published: January 2023

Abstract
T-cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. However, limited knowledge exists of the initial dynamics that establish exhaustion in humans. We studied longitudinal blood samples from a unique cohort of primary HCV infection subjects using single cell multi-omics and viral dynamics to identify the functions and phenotypes of HCV-specific CD8+ T cells.
The magnitude of IFN-γ production against the transmitted virus was associated with the rate of immune escape, larger clonal expansion, and a molecular profile consistent with a progenitor of early-exhaustion. Lineage tracing within clones revealed fate plasticity through the course of the infection and differentiation fates of progenitor exhausted subsets. This study provides new insights on the contribution of CD8+ T cells to HCV disease outcome and exhaustion, and supports future studies on early T-cell differentiation in human infections.
Supported by grants from the NHMCR and scholarships from the Australian Government Research Training Program.
Homeostatic cytokines regulate the emergence of human prenatal effector T cells.
Authors: Locher Veronica , Park Sara , Bunis Daniel , Makredes Stephanie , Fragiadakis Gabriela , Halkias Joanna 
Published: January 2023

Abstract
In a healthy pregnancy, prenatal immunity promotes tolerance in utero and transitions to provide protective immunity after birth. In pathologic pregnancies, in utero immune activation and the ensuing fetal inflammatory response are predictive of severe neonatal morbidity and mortality. We previously demonstrated that the majority of prenatal intestinal memory CD4 T cells express the transcription factor PLZF and possess a heightened Th1 effector potential. These PLZF+ CD4+ T cells specifically accumulate in the intestine, are absent from the adult, and are enriched in the cord blood of infants exposed to in utero inflammatory pathology. However, the signals that drive their intestinal accumulation and maturation are not well understood. We show that PLZF+ CD4+ T cells are MHC Class II restricted and display tissue specific functional heterogeneity, including Th2-, Th22- and Th17-like capacities. We provide evidence that differences in homeostatic cytokines between the small intestine and mesenteric lymph node support the preferential accumulation and functional compartmentalization of prenatal PLZF+ CD4+ T cells. Specifically, we show that IL-7 and TGFβ reciprocally modulate the preferential expansion and functional maturation of PLZF+ CD4+ T cells. We provide evidence for the generation of both virtual memory T cells as well as classic antigen driven differentiation of Th1- and Th17-like effector PLZF+ CD4+ T cells. This work identifies critical mechanisms of human prenatal immune maturation and regulation and could inform the development of novel therapeutic strategies to address perinatal inflammatory pathologies.
Supported by K08 Mentored Clinical Scientist Development Award (AI128007) to Joanna Halkias and the Burroughs Wellcome Fund Preterm Birth Initiative (1019828)
Impact of TCR-peptide/MHC class II affinity on the pathogenicity and regulation of prostate-specific CD4+ T cells
Authors: Rodriguez Donald M , Duncombe Ryan , Lee Victoria , Zeng Sharon , Klawon David E J , Adams Erin J , Savage Peter Aidan 
Published: January 2023

Abstract
In both humans and mice, self-reactive CD4+ T cells are implicated in a range of autoinflammatory processes. To promote disease, such cells must evade clonal deletion in the thymus, as well as intrinsic and extrinsic regulation mechanisms in the periphery, including anergy and regulatory T cell-mediated suppression. However, the impact of T cell receptor (TCR) - peptide/MHC class II (pMHCII) binding properties on the autoimmune potential of self-specific cells and their susceptibility to immune regulation remains incompletely defined. Much previous work on this topic has relied on the study of T cells reactive to foreign model antigens. However, immune responses towards such antigens may not recapitulate those targeting bona fide self-antigens. Through the in vivo analysis of CD4+ T cell clones reactive to a natural I-Ab-restricted self-peptide derived from the prostate-specific protein Tcaf3 (termed “C4” peptide), we aim to define the role of TCR-pMHCII binding affinity on the pathogenicity and regulation of self-reactive CD4+ T cell clones. Our findings thus far in both tumor-free and prostate-tumor-bearing mice reveal notable differences in the developmental trajectories and peripheral functions of clones with varying TCR affinity for C4/I-Ab. Ongoing work will continue to leverage our novel and physiologically relevant TCR-ligand system to better understand the fundamental mechanisms by which immune tolerance is established and enforced.
This work was funded by the following sources (to P.A.S.): R01-CA160371, R01-AI110507, U01-AI154560, a Cancer Research Institute Investigator Award, and the University of Chicago Comprehensive Cancer Center. D.R. was supported by an NIH/NCI F30 predoctoral fellowship (F30-CA247264). V.L. was supported by an NIH/NCI F30 predoctoral fellowship (F30-CA217109). D.R. and V.L. were supported by the University of Chicago Medical Scientist Training Program (T32-GM007281).