bluuebunny/crossref_metadata_2025_split huggingface dataset:
Varying pMHC-TCR affinity at the memory checkpoint alters the number and phenotype of memory CD4 T cells.
Authors: Jones Michael C. , Devarajan Priyadharshini , Nanaware Padma Pandurang , Stern Lawrence J. , Huseby Eric S. , Swain Susan L. 
Published: January 2023

Abstract
We have defined a memory checkpoint, 5–7 days post infection (dpi) with influenza A virus (IAV), during which responding CD4 effector cells need to re-encounter their cognate antigen (Ag) to effectively transition to memory. Ag encounter during this checkpoint promotes CD4 effector and memory survival, cytokine production potential, and leads to enhanced protection against lethal IAV challenge. Activated APC, pulsed with peptide, are sufficient to drive effectors to memory in vivo. Therefore, we can determine what influence Ag dose and affinity, at the effector stage, have on memory generation. We have developed an IAV-specific TCR transgenic mouse with CD4 T cells specific for an immunodominant, highly conserved, influenza nucleoprotein determinant (NP311–325). Using several altered peptide ligands with varying affinities that activate the transgenic CD4 T cells to varying degrees, we can analyze how varying pMHC-TCR affinity at the memory checkpoint influences the generation of the CD4 memory population. Our preliminary data indicate that when CD4 T cells encounter high, as compared to the medium and low affinity peptides during the memory checkpoint, they more efficiently develop into memory cells. If high affinity and/or dose of peptide is needed, it would imply continuing infection at the checkpoint is optimum for generating CD4 memory and should inform the kind of vaccine strategies that can successfully mimic live infection.
Defining the role of CD69 in the formation of resident memory CD8+ T cells
Authors: Walsh Daniel , da Silva Henrique Borges , Beura Lalit , Breed Elise , Ruscher Roland , Peng Changwei , Hamilton Sara E. , Masopust David , Jameson Stephen 
Published: January 2023

Abstract
Resident memory CD8+ T cells (TRM) reside in nonlymphoid tissues. There, they play a key role in preventing reinfection by exerting cytotoxic and inflammatory functions upon exposure to previously encountered pathogens. CD69 is often used as a definitive marker of TRM cells. CD69’s interaction with the G-protein-coupled receptor S1PR1 has been identified as one mechanism by which CD69 can regulate tissue residency. However, the functional requirement for CD69 in promoting the generation and maintenance of CD8+ TRM under a wide variety of circumstances remains unclear. We explored the role of CD69 in tissue residency using co-transfer of antigen specific CD69 sufficient and deficient CD8+ T cells in the context of acute LCMV, Influenza, and VSV infections. Strikingly, we found that CD69 was not necessary for TRM establishment in most tissues, although it can promote TRM localization under some circumstances. This seems to be influenced by the focal point of infection. Interestingly, the kidney appears to rely on CD69 for tissue residency with every model pathogen examined. We propose that the requirement for CD69 is context dependent rather than absolute, and that a combination of factors, including tissue microenvironment and infectious agent, dictate CD69’s influence on development of CD8+ resident memory.
Antigen recognition by CD8+ T cells in non-lymphoid tissues initiates a transcriptional program of tissue-resident memory differentiation
Authors: Hobbs Samuel J. , Nolz Jeffrey C. 
Published: January 2023

Abstract
Tissue-resident memory (TRM) CD8+ T cells permanently reside in non-lymphoid tissues where they are important mediators of both host defense and inflammatory disease. TRM cells are derived from effector cells after they have entered non-lymphoid tissues, but the mechanisms that control TRM differentiation are largely undefined. We have recently used a model of localized epicutaneous infection with Vaccinia viruses (VacV) expressing unique model antigens to demonstrate that antigen recognition in the skin microenvironment enhances TRM formation by ~50–100 fold. To understand how T cell receptor (TCR) engagement may promote TRM differentiation, we sought to identify CD8+ T cells that were actively recognizing cognate peptide-MHC in vivo. Using an endogenous interferon-gamma (IFNγ)-YFP reporter, we found that only ~20% of the antigen-specific CD8+ T cells in the skin microenvironment produce IFNγ during a VacV skin infection. However, genome-wide transcriptional profiling revealed that the T cells producing IFNγ in the skin were also undergoing changes in gene expression that resemble mature TRM cells. In fact, IFNγ+ CD8+ T cells also expressed the transcription factor Blimp1, which has been shown to be critical for the acquisition of the core TRM transcriptional profile. TCR stimulation induced Blimp1 expression in effector, but not naïve, CD8+ T cells, suggesting that a secondary antigen encounter promotes unique transcriptional programming when recently activated CD8+ T cells exhibit their effector functions. Thus, antigen recognition by effector CD8+ T cells in non-lymphoid tissues is a critical factor impacting gene expression, which ultimately promotes the differentiation of TRM cells during viral skin infection.
Interleukin-1 and IL-23 induce innate-like immune responses by bystander-activated memory CD4+ T cells contributing to the autoimmune pathogenesis
Authors: Lee Hong-Gyun , Lee Jae-Ung , Kang Insoo , Choi Je-Min 
Published: January 2023

Abstract
Antigen-nonspecific bystander activation of CD4+ T lymphocytes have been recently discovered. However, the immunopathological role of non-specific bystander activated CD4+ T cells responding to pro-inflammatory cytokines remains unknown. Here, we show that IL-1β acted directly on polyclonal memory, but not naïve, CD4+ T cells in synergy with IL-23 to promote IL-17A and IFN-γ expression in both mice and human. This bystander CD4+ T cell activation is dependent on IL-1 but not T cell antigen receptors (TCRs). In vivo, co-transfer of MOG-specific TCR transgenic (2D2) naïve T cells with MOG-nonspecific TCR transgenic (OT-II) memory-like Th17 cells increased susceptibility to EAE. IL-1 dependent MOG-nonspecific memory-like Th17 cells infiltrated to the CNS producing IL-17A, IFN-γ, and GM-CSF, which made important contributions to the development of autoimmune neuroinflammation. Our findings demonstrate that IL-1β and IL-23 activates TCR-independent innate-like immune responses by bystander activated memory CD4+ T cells contributing to the autoimmune disease pathogenesis.
TLR2-dependent bystander activation of T cells results in exacerbation of Lyme arthritis
Authors: Whiteside Sarah , Snook Jeremy P. , Ma Ying , Sonderegger F. Lynn , Fisher Colleen , Petersen Charisse , Zachary James F. , Round June L. , Williams Matthew A. , Weis Janis J. 
Published: January 2023

Abstract
Infection with the bacteria Borrelia burgdorferi results in a multidimensional disease including, fever, headache, arthritis, and a characteristic skin rash. When left untreated, bacteria can disseminate to multiple parts of the body including joints, heart, and nervous system. Approximately 10–20% of patients treated with antibiotic therapy for Lyme disease will continue to have persistent symptoms for months or years. T cells predominate the immune response in the synovial fluid of these patients; however, their role in Lyme disease remains poorly defined. Using a murine model of persistent Lyme arthritis, we observed that bystander activation of CD4+ and CD8+ T cells leads to the secretion of arthritis-promoting IFN-γ, similar to the inflammatory environment seen in the synovial tissue of patients with post-treatment Lyme disease (PTLD). T cell receptor (TCR) transgenic mice containing monoclonal specificity towards non-Borrelia epitopes confirmed that bystander T cell activation was responsible for disease development. RNA-sequencing of bystander activated T cells provided insight into the molecular characteristics of non-classical T cell activation. The microbial pattern recognition receptor Toll-like receptor 2 (TLR2) was upregulated on T cells following infection, implicating it as marker of bystander T cell activation. In fact, T cell intrinsic expression of TLR2 contributed to IFN-γ production and arthritis, providing a mechanism for microbial-induced bystander T cell activation during infection. These results reveal a novel TLR2-intrinsic role for T cells in Lyme arthritis, with potentially broader application to bystander T cell activation and immune pathogenesis.
Mda5/MAVS signaling is essential for resistance against Aspergillus fumigatus
Authors: Obar Joshua J. , Caffrey Alayna Katherine , Wang Xi , Espinosa Vanessa , Tang Yi-Wei , Hohl Tobias , Rivera Amariliz , Cramer Robert 
Published: January 2023

Abstract
Type I and III interferons act as important activators of antifungal neutrophil response in the lungs. The RIG-I like receptor (RLR) family, including RIG-I and Mda5, are cytosolic RNA sensors that signal through the MAVS adaptor in order to activate interferon responses against viruses. Whether the RLR family has broader effects on host immunity against other pathogen families remains to be fully explored. Herein we demonstrate that Mda5/MAVS signaling was essential for host resistance against pulmonary Aspergillus fumigatus challenge through the regulation of antifungal leukocyte responses. Aspergillus fumigatus induction of type I interferons was partially dependent on Mda5/MAVS signaling, while type III interferon expression was entirely dependent on Mda5/MAVS signaling. Activation of the interferon pathway was driven by prolonged exposure to fungal spores, rather than germ tubes. Ultimately, interferon signaling drove the expression of CXCL9 and CXCL10, SNPs in the latter are associated with invasive aspergillosis in human patients. Our data suggest a broader role of the RLR family in the regulation of innate immunity to include invasive fungal infections.
The influence of gammaherpesvirus co-infection on malaria immunopathogenesis and parasite control
Authors: Netongo Palmer Masumbe , Mimche Patrice Nsangou , Matar Caline G. , Speck Samuel H. , Lamb Tracey J. 
Published: January 2023

Abstract
Malaria still kills up to 500,000 people annually. Risk factors contributing to severe disease remain poorly understood. There is compelling evidence that acute gammaherpesvirus such as Epstein-Barr Virus (EBV) coinfections are responsible for suppressing the development of humoral immunity during Plasmodium infection in children and may constitute a salient risk factor for disease severity. However, the actual mechanisms by which protective humoral immune responses to Plasmodium infection are suppressed by gammaherpesviruses are incompletely understood. It has previously been shown that acute MHV68 co-infection resulted in the transformation of a non-lethal Plasmodium yoelii XNL infection into a lethal one in C57BL/6 mice, an outcome linked to a defect in the maintenance of germinal center B cells and T follicular helper cells (Tfh) cells in the spleen and a defect in antibody production. Since the suppressive effect requires the M2 latency associated protein of MHV68, and M2 induces IL-10 secretion from the B cells it infects, we tested the hypothesis that the induction of IL-10 by M2 in MHV68-infected B cells impairs the ability of T follicular helper cells (Tfh) to provide B cell help for effective, broad spectrum antibody production to incoming Plasmodium infection. We tested our hypothesis by co-infecting mice that cannot produce IL-10 from B cells (IL-10Flox_CD19 Cre+), and measured the effect that this defect has on Tfh maintenance, plasma cell formation and antibody production in response to Plasmodium infection. Our findings suggest B cell derived IL-10 is an important component of MHV68-mediated disruption in germinal center formation during gammaherpesvirus/ Plasmodium co-infections.
Coinfection: influenza A virus and Aspergillus fumigatus
Authors: Rippee-Brooks Meagan D. , Lupfer Christopher R. 
Published: January 2023

Abstract
Bacterial coinfections with influenza A virus (IVA) are extremely serious and life-threatening. However, there exists limited data gathered about the importance of fungal infections with IAV. Clinical case reports indicate that fungal coinfections do happen and suggest the pandemic 2009 IAV has a propensity to predispose patients to secondary fungal infections more than previous IAV strains. However, the factors involved remain to be determined. We have developed an in vitro model using primary mouse bone marrow derived macrophages infected with IVA and coinfected with the opportunistic fungal pathogen Aspergillus fumigatus. Our results indicate that IVA and fungal coinfections synergistically enhance cell signaling and cytokine production. We propose this exacerbated immune response during IVA and A. fumigatus predisposes clinical patients to more severe pneumonia, and we seek to identify the pathways responsible for the heightened cytokine responses and their significance in vivo.
Investigating local and systemic immune changes following sub-chronic inhalation of Aspergillus versicolor spores
Authors: Barnes Mark A. , Croston Tara L. , Lemons Angela R. , Beezhold Donald H. , Green Brett J. 
Published: January 2023

Abstract
Fungi are environmentally ubiquitous, and can be particularly abundant in damp indoor locations which may lead to pulmonary fungal exposure via inhalation of bioaerosols. Some of the adverse pulmonary health effects associated with fungal challenges include asthma, allergy, hypersensitivity pneumonitis, and local or disseminated infection. Here, we study the innate immune effects following 13 weeks sub-chronic inhalation exposures to spores derived from a common indoor fungal contaminant, Aspergillus versicolor. Compared to air-only control mice, A. versicolor-exposed B6C3F1 mice exhibited increased recruitment of leukocytes to the lung, particularly eosinophils and type 2 innate lymphoid cells (ILC2s), but also alveolar macrophages, inflammatory monocytes, and neutrophils following 13 weeks of exposure in nose-only inhalation chambers. Local expression of ccl2, ccl7, eotaxin, and il13 mRNA was increased in lung tissue. In addition, IL-4, CCL3, CCL4, CXCL1, and CXCL5 were increased in bronchoaveolar lavage fluid of A. versicolor-exposed mice compared to controls. Systemically, circulating CCL7, CXCL1, CXCL5, and CXCL10 were increased in serum of mice following inhalation of spores. Taken together, these data indicate A. versicolor elicits a Th2-biased immune response that is driven by multiple innate immune cell populations, including monocytes, eosinophils, and ILC2s.
The role of transcription factor T-bet in B cell mediated responses to Plasmodium infection
Authors: Cimperman Clare K. , Sheehan Patrick W. , Theall Brandon P. , Pena Mirna , Pierce Susan K. , Akkaya Munir 
Published: January 2023

Abstract
Malaria is a global health concern which affects over 200 million individuals worldwide. Although the immune system rapidly responds to Plasmodium infection with specific antibodies, natural antibodies fail to establish long term protection, often leading to repetitive infections and chronicity. Recent studies showed that in a chronic malaria setting both B cells and T cells induce expression of T-bet transcription factor. It is not completely understood whether this is a part of the specific host defense or a result of disease pathogenesis. Here using transgenic mouse models, we show that knockout of T-bet or IFN-g similarly reduces survival of mice compared to WT upon infection with Plasmodium chabaudi, therefore suggesting a protective role for T-bet. To determine the specific role T-bet plays in B cell responses to Plasmodium, we first identified that T-bet expression in mouse B cells are triggered by dual stimulation of IFN-g and B cell receptor. Similarly using Tbet-zsgreen transgenic mice we showed that conditions specific to Plasmodium chabaudi infection drive T-bet expression in multiple B cell subsets in a time dependent fashion. However, no such induction is shown when mice are immunized with T-dependent protein antigens adjuvanted with Alum. On the other hand, bone marrow chimeric animals reconstituted with equal amounts of congenically labeled WT and T-bet KO bone marrow cells showed that for most B cell subsets the lack of T-bet does not change the ratio of WT and KO cells upon Plasmodium infection indicating that T-bet expression may not be equally critical for all B cell responses to infection. These findings suggest a complex role of T-bet in the development of humoral responses.
Acute high fat diet disrupts intestinal barrier repair
Authors: McAlester Andrea Hill , Kim Myunghoo , Song Rachel (Hyo) , Wu Wan-jun , Diehl Gretchen 
Published: January 2023

Abstract
Over-consumption of high fat diets (HFD) corresponds to increased incidence and severity of many chronic inflammatory diseases, including those of the intestinal tract. The impact of HFD feeding on bodily tissues has largely been studied in the context of obesity. Long-term exposure to HFD has been shown to decrease barrier function, allowing for bacterial penetration into the body resulting in chronic inflammation. However, this effect is secondary to adipose tissue dysfunction making it difficult to determine the direct impact of HFD on intestinal barrier function.
The intestine acts as a protective barrier and our immune system supports the proper functioning of this barrier, aiding in protection from pathogens. Sustained damage or loss of proper barrier function can result in chronic inflammation and diseases such as inflammatory bowel disease (IBD). We hypothesized that intestinal exposure to HFD would directly alter the intestinal barrier resulting in enhanced inflammation.
To test this, we utilized short-term HFD feeding in the context of mouse models of colitis. Our data demonstrates that HFD increases susceptibility to colitis with increased weightloss, aberrant epithelial cell proliferation, loss of goblet cells and the mucus layer necessary to prevent microbial penetration into the body. We also identified dysregulated immune responses resulting in an inability of intestinal immune cells to properly support barrier function and repair. Together, we find that HFD feeding directly promotes altered functions of intestinal epithelial and immune cells leading to a barrier repair defect resulting in an inability to repair epithelial damage and increasing pathology in models of IBD.
Interactions between microbiota and the teleost immune system in health and disease
Authors: Salinas Irene , Casadei Elisa , Takizawa Fumio , Shibasaki Yasuhiro , Sunyer Oriol J. 
Published: January 2023

Abstract
The symbiosis between metazoans and prokaryotes is one of the most ancient and successful relationships found in nature. Mucosal surfaces are the main interface between animal hosts and their environment, and these surfaces are colonized by unique microbial communities that shape every physiological system of the host. Teleost fish have both an innate and adaptive immune system and are the most ancient vertebrates with a dedicated mucosal immunoglobulin (Ig), known as IgT/IgZ. IgT is secreted via the polymeric Ig receptor across teleost mucosal epithelia, including the gills, skin, nose and gut. Recent studies have shed light on the interactions between mucosal Igs and microbiota in teleosts both during health and disease. Teleost fish symbiotic bacteria are coated by both secretory Igs (sIgT and sIgM) as well as pIgR. Using two different models, a stress model and an IgT depletion model, we provide evidence that any alterations in the levels of mucosal Igs result in different states of dysbiosis in rainbow trout (Oncorhynchus mykiss). Dysbiosis in trout is characterized by losses of certain taxa and subsequent invasion of new species in several mucosal sites. Unlike in mammalian models of IgA deficiency, where IgM compensatory responses occur, no compensatory IgM or IgD responses were observed in IgT-depleted rainbow trout. These results demonstrate that teleost fish, similar to mammals, utilize specialized mucosal Igs to maintain harmonic relationships with symbiotic bacteria.
Commensal gut fungi regulate susceptibility to colitis and colorectal cancer.
Authors: Malik Ankit , Sharma Deepika , Vogel Peter , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
The cross-talk between innate immune sensors and commensal microbes in the gut is crucial for maintaining intestinal barrier homeostasis. Fungi represent a major component of the resident gut flora, and fungal diversity narrows during colitis and colorectal cancer pathogenesis. Mutations in the genes that encode molecules involved in the fungal sensing pathways are associated with an increased risk of developing colitis and colorectal cancer. However, the precise roles of gut fungi and associated immune recognition cascade in colitis and colorectal tumorigenesis are not well established. We show here the role of commensal fungal sensing by CLR signaling pathway in the regulation of inflammation and tumorigenesis in the colon.
Isoprenol-Induced Neuroprotection in Experimental Multiple Sclerosis
Authors: Ochoa-Reparaz Javier , Strawn Kevin D. , Kirby Trevor O. , Brown Madalyn N. , Walters Dana C. , Gibson K. Michael , Roullet Jean-Baptiste 
Published: January 2023

Abstract
Farnesol is a 15-carbon organic acyclic sesquiterpene alcohol (isoprenol) produced by plants and animals. It is a potent blocker of neuronal voltage-gated Ca2+ found in the human brain. It has potent anti-oxidant and antiinflammatory effects in vitro, and neuroprotection based on the regulation of free radicals production by glial cells was demonstrated in a murine model of neurotoxicity. Because inflammation, oxidative stress and intraneuronal Ca2+ overload are associated with central nervous system (CNS) demyelinating diseases, we sought to determine if farnesol treatment would result in protection against experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). We compared the progression of EAE in C57BL/6 mice treated orally with farnesol (100 mg/kg/daily by gavage in olive oil) versus EAE progression in untreated mice (control) (n = 10/group). Treatment started at EAE induction and continued for 25 days. EAE clinical severity was monitored daily. Factorial repeated measures ANOVA of the scores showed: 1) a significant Day effect (disease onset 9 days after induction), 2) a significant Group effect (approx. 80% reduction in scores in the Farnesol group), and 3) a significant Day * Group interaction with scores being significantly lower in the Farnesol group every day starting one day after disease onset. At day 25, 50% of control mice had been euthanized due to scores ≥ 3.5 vs. none in the Farnesol group. Our results indicate that Farnesol significantly reduces disease onset in EAE. Studies to elucidate the mechanism of action of farnesol, screening of structural analogues of farnesol for anti-EAE activity, and assessment of farnesol therapeutic efficacy in other animal models of MS are being conducted.