bluuebunny/crossref_metadata_2025_split huggingface dataset:
T cell receptor signaling and Toll-like receptor signaling converge to amplify T cell responses
Authors: Young Mary H , Navarro Garnet , Askovich Peter , Aderem Alan 
Published: January 2023

Abstract
Toll-like receptors (TLRs) are an essential part of the innate immune system. Their function on antigen presenting cells helps drive efficient T cell responses to pathogens. However, T cells also express several TLRs. Additionally, many of the downstream signaling components of TLRs are shared with those of the T cell receptor. Our hypothesis is that these two pathways work in concert to exert unique and potent T cell responses. We have found that several TLRs are able to enhance T cell responses, including TLR3, TLR4, TLR7, and TLR9. We have found that TLR7 signaling, in particular, synergizes with TCR activation and improves T cell effector functions. Priming T cells with synthetic and natural TLR7 ligands before TCR ligation further boosts T cell responses. The combination of TLR7 and TCR stimulation in T cells enhances cytokine production and proliferation in T cells. We identified several overlapping components between TLR7 and TCR activation pathways by gene expression, which may provide combinatorial increases in T cell activation. In addition, we found increases in anti-viral response pathways that are atypical in T cells. This response was unique to the combination of TLR and TCR stimuli. Thus, we wanted to determine if TLR7 signaling in T cells is important during an acute infection. During influenza, T cell-specific loss of TLR7 alters infection dynamics in the T cell population, resulting in significant activation delays and abnormalities. These findings show that TLR7 is important in normal T cell responses to viral infections. Understanding the contribution of TLR signaling to T cell activation will be useful in guiding enhanced vaccine strategies.
IL-4 sensitivity shapes the peripheral CD8+ T cell pool and response to infection
Authors: Renkema Kristin , Lee June-Yong , Lee You-Jeong , Hamilton Sara , Hogquist Kristin Ann , Jameson Stephen 
Published: January 2023

Abstract
Previous studies have revealed that a population of innate memory CD8+ T cells is generated in response to IL-4, first appearing in the thymus and bearing high expression levels of Eomesodermin (Eomes) but not T-bet. However, the antigen specificity and functional properties of these cells is poorly defined. Here we show that IL-4 regulates not only the frequency and function of innate memory CD8+ T cells but also regulates Eomes expression levels and functional reactivity of naïve CD8+ T cells. Lack of IL-4 responsiveness attenuates the capacity of CD8+ T cells to mount a robust response to LCMV infection, with both quantitative and qualitative effects on effector and memory antigen specific CD8+ T cells. Importantly, our data revealed that these effects of IL-4 exposure occur prior to, not during infection. Together, these data show that IL-4 influences the entire peripheral CD8+ T cell pool, influencing expression of T-box transcription factors, functional reactivity and the capacity to respond to infection. These findings indicate that IL-4, a canonical Th2 cytokine, can sometimes promote rather than impair Th1-type immune responses.
Smad4 Signaling is Important for Generation of Teff Cells but not Protection
Authors: Hu Yinghong , Suarez-Ramirez Jenny , Cauley Linda S 
Published: January 2023

Abstract
Ideally, vaccines for pulmonary infections should generate protective populations of anti-viral memory CD8 T cells without accompanying responses by pathogenic effector T (Teff) cells. With this goal in mind, we examined the influence of transforming growth factor β (TGFβ), and the downstream molecule Smad4, during CD8 T cell differentiation. CTLs lacking the TGFβ receptor preferentially expressed KLRG1 after influenza virus infection indicating the presence of highly differentiated Teff cells, while differentiation of CD103+ tissue resident memory T (Trm) cells was completely abrogated. In contrast, Smad4-deficient CD8 T cells preferentially acquired a KLRG1-negative phenotype, while CD103 was aberrantly expressed on CTLs in other tissues. Smad4-deficency caused slightly delayed viral clearance after primary IAV infection, but was not required for protective immunity upon reinfection with another strain. Our data indicate that Smad4 dictates the fate decision of activated CTLs by integrating signals from multiple environmental stimuli to promote TEFF generation.
Inhibition of Cdk2 promotes the generation of inducible CD8+ T regulatory cells by abrogating binding of the EZH2 methyltransferase on the Foxp3 promoter.
Authors: Li Lequn , Barchan Kankana , Weaver Jessica D , Patsoukis Nick , Boussiotis Vassiliki A 
Published: January 2023

Abstract
Cdk2 has a central role in cell cycle re-entry and Cdk2 inhibition is mandatory for induction of T cell tolerance. To determine the effect of Cdk2 inhibition on T cell alloresponses we used the B6D2F1 model of bone marrow transplantation (BMT) and two Cdk2 inhibitors (Cdk2i), CYC202 and CYC205. B6D2F1(Kd) recipients infused with BM and T cells from C57BL/6(Kb) donors were treated with each Cdk2i for 3 weeks and graft versus host disease (GvHD) was assessed over a 70-day period. Cdk2i treatment decreased GvHD mortality (p=0.0054). To examine if Cdk2i affected Treg differentiation we used T cells from Foxp3.GFP-KI mice during BMT. Cdk2i-treated recipients had no difference in CD4+GFP+ Treg compared to control groups in peripheral blood, splenocytes, lymph nodes and intestinal lymphoid cells (ILC) but had increased CD8+GFP+ Treg, predominantly in ILCs (p=0.05). In Treg polarizing culture Cdk2i had only minimal effect on CD4+GFP+ cells but induced significant increase of CD8+GFP+ cells. However, TGF-b-mediated signaling, as determined by Smad3 phosphorylation was unaffected. FOX family members are regulated by transcriptional and epigenetic mechanisms. The Polycomb group (PcG) protein, enhancer of zeste homologue 2 (EZH2) induces histone H3 lysine 27 trimethylation (H3K27me3) and epigenetic gene silencing. Cdk2 phosphorylates EZH2 Thr350, which is important for maintenance of H3K27me3 at EZH2 target loci. We determined that Cdk2i inhibited EZH2 Thr350 phosphorylation in CD8+ T cells, which coincided with increased Foxp3 expression. ChIP-PCR identified EZH2 binding on three sites of Foxp3 promoter, which was abrogated by Cdk2i. Thus, Cdk2 inhibition induces CD8+ Treg via EZH2-mediated epigenetic mechanisms.
Using patients’ stated preferences for immunoglobulin therapies to evaluate administration features in current treatments
Authors: Runken Michael Chris , Gonzalez Juan Marcos 
Published: January 2023

Abstract
In 2012, Mohamed et al.(J Med Econ) estimated preference weights for changes in the administration features of immunoglobulin (IG) therapies among patients with self-reported primary immunodeficiency disorder (PIDD). The preference weights were estimated using a discrete-choice experiment survey that asked respondents to choose between hypothetical treatments with varying administration features. However, the authors did not discuss the implications of their results on patients’ preferences for currently available IG therapies with specific combinations of the elicited features.
Transferring preference results from Mohamed et al. allowed us to evaluate current treatment options not considered during the original study. This transfer of preference information is commonplace in economics, but not in health applications where it is done almost exclusively with treatment outcomes and not treatment administration features.
The aim of this study was to assess patients’ relative preferences for currently available IG treatments in terms of their administration features as elicited by Mohamed et al. To achieve this objective, we approximated a preference-weight function through visual examination of the weights plotted in the publication. This function provides a calculation of preference scores for any IG treatment described with the attributes studied in Mohamed et al.
This research suggests a general tendency in PIDD patients to prefer the administration features associated with intravenous therapies over subcutaneous therapies. The evaluation of IG therapies with the approximated preference function highlights how attribute preferences can be considered jointly in clinically meaningful treatment profiles.
Hypersplenism, EPO resistance and chronic Salmonella infection
Authors: Loomis Wendy P , Delaney Martha A. , Johnson Matthew L. , Cookson Brad T 
Published: January 2023

Abstract
Chronic diseases, such as AIDS and malaria, are associated with increased susceptibility to non-typhoidal Salmonella (NTS) infection. Among the key clinical manifestations shared by these immunocompromised individuals are anemia and splenomegaly (i.e. hypersplenism), conditions also associated with NTS susceptibility. To better understand the immunological basis of hypersplenism, we developed a model of chronic NTS infection in resistant 129X1/SvJ mice transiently depleted of CD4+ T cells. NTS infection induced chronic peripheral anemia that became more severe in the absence of CD4+ T cells. While serum erythropoietin (EPO) peaked on day 21 post infection in mock-depleted mice, EPO levels continued to rise in CD4-depleted animals. The failure to resolve anemia despite high levels of EPO parallels the development of EPO resistance in patients receiving recombinant human EPO therapy. Increased accumulation of mature erythrocytes and immature erythroid precursor cells within the enlarged spleens of CD4-depleted mice suggests that chronic inflammation leads to splenic sequestration of damaged erythrocytes, thus contributing to persistent anemia. We demonstrate that sequestration of erythroid cells drives the expansion of splenic macrophages, a known reservoir for NTS survival. Our findings provide a potential mechanism to link anemia of chronic disease, hypersplenism and increased susceptibility to NTS infections.
CD169+ marginal zone macrophages orchestrate innate immune responses to bacterial infection.
Authors: Perez Oriana A , Qiu Zhijuan , Romagnoli Pablo A , Benechet Alexandre P , Maher Leigh , Tanaka Masato , Khanna Kamal Mohan 
Published: January 2023

Abstract
The spleen is an important site for generating protective immune responses against pathogens. Immune cells in the spleen undergo rapid reorganization to initiate and maintain local inflammatory responses against pathogens. How the spatial dynamics of cellular communication are regulated in the spleen after infection remains unclear. Respectively, CD169+ macrophages are a population of tissue resident macrophages that are positioned in the marginal zone to rapidly encounter invading pathogens. However, the role of splenic CD169+ macrophages during infections is not well understood. Here we show that splenic CD169+ macrophages serve as a primary cellular host to blood-borne bacteria Listeria monocytogens (Lm) and are also essential for the clearance of other bacterial and viral pathogens. In addition to controlling initial bacterial growth, CD169+ macrophages orchestrated a second phase of innate protection by mediating the transport of Lm to the splenic T cell zones and driving the subsequent reorganization of neutrophils, monocytes, and NK cells into hierarchical clusters. Specifically our study revealed that bacterial transport to the T cell zones was mediated by trans-infection of closely interacting CD8α+ DCs with Lm-infected CD169+ macrophages. Although, CD8α+ DCs are required for a productive Lm infection in the spleen, to our surprise mice that lacked both CD8α+ DCs and CD169+ macrophages were unable to control Lm infection. These results demonstrated that CD169+ macrophages regulated bacterial access to the pathogen favorable CD8α+ DC niche, ultimately providing a rationale for reassessing the current paradigm regarding the temporal role of CD8α+ DCs during Lm infection.
Identification of two T cell subsets that protect and survive long-term in malaria infection
Authors: Opata Michael , Norwood Karis , Ibitokou Samad A , Carpio Victor Hugo , Wilson Kyle , Dillon Brian , Stephens Robin 
Published: January 2023

Abstract
Malaria and other chronic infections generate effector and effector memory T cells, but the infection is not completely controlled. While the parasite is present, some level of protection is provided, but this decays as specific cytokine production disappears. This indicates that protection in chronic malaria is partly provided by continuously activated CD4 T cells. Current vaccination protocols also result in immunity that decays. In order to invent new vaccination strategies to combat this problem, we need to understand what T cell types are potentially both protective and long-lived. Therefore, we tested effector (Teff), central (Tcm), and effector memory (Tem) T cell subsets for their ability to both protect and survive in vivo. Using transgenic T cells specific for the Merozoite Surface Protein-1 of Plasmodium chabaudi, and our previously defined effector and memory subsets, we sort-purified individual cell populations, and tested their ability to protect in combination with immune B cells. Strikingly, Teff reduce parasitemia by half, at all stages of effector maturation. When Teff subsets were rested in naïve animals to allow generation of memory, the least mature Teff subset, TeffEarly, which we have shown generate the most memory cells, decreased parasitemia the most on infection of adoptive hosts. Interestingly, these earliest activated T cells survive as well as the memory subsets, of which only Tem Late (CD62LloCD27−) reduced parasite by 10%. Therefore, we have identified two long-lived T cell subsets that may represent a correlate of protection or a target for longer-lived vaccine-induced protection against malaria.
Lactic acid suppresses cytokine production and expression of miR-155 and 146a following LPS activation in mast cells.
Authors: Caslin Heather , Abebayehu Daniel , Qayum Amina Abdul , Spence Andrew , Ryan John J 
Published: January 2023

Abstract
A considerable health burden, sepsis is a clinical inflammatory condition with mortality rates from 30–50% and no effective treatments. Septic patients and animal models show increased blood lactate concentrations and microRNA(miR)-155 and miR-146a expression, but how these factors are related is not clear. Lactic acid has been shown to have a suppressive effect on LPS activation and subsequent NFkB induction in macrophages and dendritic cells, but mast cells have not been examined. Our data suggests that lactic acid suppresses LPS-induced cytokine and chemokine production in bone marrow derived mast cells (BMMCs) and peritoneal mast cells. This effect is dependent upon the concentration of lactic acid, pH, and transport through MCT-1. Additionally, it is known that miR-155 and 146a affect cytokine production downstream of NFkB and TLR4, however the effects of lactic acid on these miRs is unknown. Our results show that LPS enhances miR-155 and miR-146a expression, an effect that is antagonized by lactic acid. Interestingly, miR-155 is historically considered pro-inflammatory, while miR-146a is considered anti-inflammatory. Current studies seek to determine the contribution of these miRs to septic inflammation and its modulation by lactic acid.
RNF144b is a negative regulator in TLR2-mediated NF-kB activation
Authors: Baek Suk-Hwan , Huang Bin , Chang Hyeun Wook 
Published: January 2023

Abstract
NF-κB regulates the expression of a various genes involved in diverse cellular processes including inflammation and immunity. Activation of NF-κB requires ubiquitination, a highly conserved and versatile modification that can regulate cell signaling through both proteasome dependent and independent mechanisms. Ubiquitination process is a representative of post-translational modification involved in NF-κB activation of TNFR and TLR signaling. We demonstrated that RNF144b, an E3 ubiquitin ligase, is important factor for the NF-κB regulation in macrophages upon stimulation with TNFa or TLR2 ligand. Treatment of TNFa or TLR2 ligand (Pam3CSK4) decreased the expression of RNF144b mRNA on macrophages. TLR2 ligand has a stronger effect than TNFa in the expression of RNF144b mRNA. Knock-down of RNF144b potentiated activation of NF-kB. And according to the increase of NF-κB activity, the formation of foam cells and the production of cytokines (IL-1β, IL-6, CCL2 and CCL3) following TLR2 stimulation increased. On the contrary, overexpression of RNF144b decreased NF-κB activity and cytokines production in the TLR2-stimuated macrophages. RNF144b binds and ubiquitinates TRAF6 and these effects are dependent of its E3 ligase activity. Mutation of Cys201 to Ala abolishes activity of RNF144b to activate TRAF6 ubiquitination and also partially attenuates NF-κB activity. Taken together, these results suggest that RNF144b stimulates NF-κB activity via TRAF6 ubiquitination and then produces inflammatory cytokines and chemokines, and eventually controls foam cell formation in the TLR2-mediated macrophages.
Autocrine and paracrine IL-2 signals collaborate to regulate distinct phases of CD8 T cell memory
Authors: Yuzefpolskiy Yevgeniy , Penny Laura Anne , Baumann Florian Martin , Smith Kendall A , Sarkar Surojit , Kalia Vandana 
Published: January 2023

Abstract
Proliferation is a defining feature of clonal cytotoxic T lymphocyte (CTL) responses upon activation. However, how proliferative events during primary expansion relate to divergent CD8 T cell fate outcomes remains poorly defined. Emerging evidence from our laboratory and others in the field suggest that death-fated effectors undergo more pronounced proliferation compared to memory-fated cells during antigen-driven T cell expansion. Adoptive transfer of activated CD8 T cell-subsets, purified based on their extent of proliferation, showed that in vivo differentiation of CD8 T cells and memory fate are linked to proliferation. We found that the less-divided effector CTL subset preferentially contributed to the central memory lineage. Interestingly, these less-divided memory precursor cells were also programmed to produce more IL-2 compared to their more-divided terminal effector counterparts. How do memory-fated cells that make their own IL-2 (a pro-proliferative cytokine) proliferate less and how does this make them better fit for the long-lived memory lineage? To answer this question, we generated CD8 T cells that could be conditionally ablated for il2. We ablated IL-2 specifically in antigen-specific CD8 T cells, during distinct phases of effector and memory differentiation. Our data showed that while paracrine IL-2 is critical for driving the early in vivo proliferative burst, the programmed life-long autochthonous IL-2 in memory-fated cells was necessary for antigen-independent maintenance, and robust secondary expansion of memory cells. Thus, autocrine and paracrine IL-2 signals collaborate during distinct stages of T cell differentiation to direct diverse CTL lineages through effects on proliferation.
Asymmetric integrin segregation regulates CD8+ T cell fate during cell division
Authors: Capece Tara , Walling Brandon Lee , Hyun Young-Min , Kim Tae-Hyoun , Lim Kihong , Kim Minsoo 
Published: January 2023

Abstract
Recent evidence suggests lineage commitment of effector and memory T cells occurs as early as the first T cell division, using the evolutionarily conserved mechanism of asymmetric cell division. In addition, successful activation of the adaptive immune response requires precise cellular localization of divided T cells in critical lymphoid niches. Although protein inheritance of asymmetrically divided T cells has been characterized and leads to two differentially fated daughter T cells, little is known about how asymmetric cell division regulates T cell migration in the lymph node and how it controls T cell differentiation. We demonstrated distinct migration and T-APC conjugation patterns and localization after the first T cell division both in vitro and in vivo. Expression of the integrin LFA-1 was the only relevant surface change during division. Using our newly generated CD11a-mYFP knock-in mice, we discovered naïve T cells reserve an intracellular store of LFA-1 located in the uropod during T cell migration. Intracellular LFA-1 quickly translocated in a Rab27-dependent manner to the cell surface within minutes of contact with antigenic stimulus. Importantly, the redistribution of both surface and intracellular LFA-1 led to a molecular asymmetry that was maintained during cell division, giving rise to daughter cells with distinct fates. We hypothesize the redistribution and asymmetric segregation of intracellular LFA-1 controls subsequent T cell encounters, localization, and cell fate.
T cell restricted Notch signaling contributes to pulmonary Th1 and Th2 polarization during Cryptococcus neoformans infection
Authors: Neal Lori M , Qiu Yafeng , Chung Jooho , Xing Enze , Cho Woosung , Malachowski Antoni , Osterholzer John J , Maillard Ivan , Olszewski Michal A 
Published: January 2023

Abstract
Notch is a key signaling pathway regulating T cell development, activation and function. Notch signaling has been shown to affect the differentiation and functional responses of Th cells in several models of infectious disease and therapeutic targeting of Notch signaling has been proposed as treatments for autoimmune diseases. However, the contribution of Notch signaling to Th cell differentiation and responses during fungal infections is unknown. To elucidate the role of Notch signaling during fungal infections we infected mice expressing a dominant negative Notch inhibitor specifically within mature T cells with the fungal pathogen Cryptococcus neoformans. Inhibition of Notch resulted in impaired leukocyte recruitment, failure to control fungal burden in the lungs and failure to prevent dissemination to the CNS. Furthermore, we show that inhibition of Notch signaling impaired both protective Th1 and non-protective Th2 anti-cryptococcal immune responses. Leukocyte cultures and T cells from Notch deficient mice produced less IFN-γ, IL-5 and IL-13 than WT cells and had reduced expression of Th1 and Th2 associated transcription factors, Tbet and Gata3. Treatment with the Notch inhibitor DAPT did not impair cytokine production in WT cells indicating that Notch impacted the differentiation of these cells rather than biasing the magnitude of responses. Th17 responses were largely unaffected by Notch; although we also measured an increase in the frequency of Tregs in Notch deprived C. neoformans infected mice. Overall, these data suggest that Notch signaling controls the differentiation of Th1 and Th2 cells during C. neoformans infection and that targeting Notch may inadvertently render hosts more susceptible to fungal infections.