bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-class PDE4D bifunctional degraders for inflammatory skin diseases
Authors: Shakya Arvind , Erdman Paul , Lai Chon , Baker Sherry , Orlandi Chiara , Greene Steven , Chaurasia Aparajita , Fung Leah 
Published: August 2023

Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by erythema and pruritis, affecting over 15 million people in the US. Th2/Th17 cytokines play a key role in AD pathogenesis, resulting in an increased inflammatory response, disrupted skin barrier, increased susceptibility to infections and allergen sensitization. Phosphodiesterase 4 (PDE4) is a cyclic 3’,5’-adenosine monophosphate (cAMP)-specific phosphodiesterase and its expression is elevated in AD patients sustaining a highly inflammatory environment. PDE4 inhibition has been shown to effectively suppress proinflammatory cytokines in clinically validated approaches for several chronic inflammatory conditions. The current standard of care therapies including PDE4 inhibitors are linked to broad adverse effects due to their off-target activities. Utilizing our proprietary PRODEGY discovery platform, we have designed potent and selective PDE4D bifunctional degraders. PDE4D degradation dramatically decreases the pro-inflammatory cytokines released by activated T cells in vitro. Additionally, PDE4D is degraded efficiently in mice spleens treated with the lead PDE4D degrader in a dose-dependent manner, with no adverse effects. Importantly, our PDE4D degraders do not induce significant degradation of known neo-substrates, suggesting high specificity. Taken together, we propose the introduction of a more potent, specific, and safe PDE4D degrader as novel therapy for inflammatory skin diseases, such as AD.
Cytokine-driven integrin expression controls CD8 T cell homeostasis
Authors: Li Can , Park Jung-Hyun 
Published: August 2023

Abstract
The peripheral CD8 T cell pool comprises a mixture of naïve and memory-phenotype (MP) cells. While naïve CD8 T cells are continuously produced and supplied through thymic export, MP CD8 T cells are mostly generated by antigen activation or cytokine-mediated differentiation and maintained by homeostatic cytokines, such as IL-15. Both naïve and MP CD8 T cells are necessary to mount vigorous immune responses against new and reoccurring pathogens. But, the mechanisms through which MP CD8 T cells would avoid competing with naïve CD8 T cells for limited space and survival cues remain largely unsolved. Here, we report that integrin CD103 plays a critical role in this process. CD103 is highly expressed on naïve CD8 T cells to mediate adhesion to cells and tissues that are abundant for its ligand, E-cadherin. Interestingly, homeostatic cytokine signaling that drives MP CD8 T cell differentiation potently downregulated the expression of CD103, dissociating them from potential competition with CD103-positive naïve CD8 T cells. Conversely, the forced expression of CD103 on MP CD8 T cells resulted in the accumulation of MP CD8 T cells and selective loss of naïve CD8 T cells. Mechanistically, we identified a subset of dendritic cells that expresses E-cadherin (E-cad+ DCs), that would interact with CD103-positive CD8 T cells to provide survival signals and control their maintenance. Collectively, our results suggest that IL-15-mediated downregulation of CD103 contributes to balancing the size and composition of the peripheral CD8 T cell pool, revealing a previously unappreciated role of cytokine-driven integrin expression in controlling CD8 T cell homeostasis.
This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.
Two developmental pathways generate functionally distinct populations of natural killer cells
Authors: Ding Yi , Lavaert Marieke , Das Arundhoti , Harly Christelle , Malin Justin , Zhao Yongge , Bhandoola Avinash 
Published: August 2023

Abstract
Natural killer (NK) cells function by eliminating virus-infected cells or tumor cells during early defenses. However, the early development of NK cells and lineage relationships between NK cells and helper innate lymphoid cells (ILCs) remain elusive. Common precursors for ILCs (ILCPs) can differentiate into both helper ILCs and NK cells. Here, we identified a NK lineage-restricted progenitor population, early NK progenitor (ENKP), which does not develop from ILCPs, thus ENKP may represent the ILCP-independent pathway of NK cell development. Competitive chimera experiment shows ENKPs generate NK cells more efficiently than ILCPs, suggesting that ENKP-dependent pathway is the major pathway for NK cell development. scRNA-seq shows ENKP-derived NK cells express Ly49 receptors and higher levels of cytotoxic genes whereas ILCP-derived NK cells have very low expression of Ly49 receptors and express higher levels of genes implicated in tissue residency such as CD69 and CD200R. Furthermore, Ly49H+ NK cells which response to MCMV infection mostly develop from ENKPs but not ILCPs. Consistently, ENKP-derived NK cells but not ILCP-derived NK cells expanded dramatically after MCMV infection. Our findings establish the existence of two pathways of NK cell development that generate functionally distinct NK cell subsets.
Normalizing pathogen exposure via pet shop mouse cohousing leads to preferential maintenance of long-lived effector memory CD8 T cells
Authors: Lucas Erin D , Huggins Matthew A , Pierson Mark , Hamilton Sara 
Published: August 2023

Abstract
Studies of the CD8 T cell memory compartment in mice have primarily been done in young mice maintained in specific pathogen free (SPF) environment. The murine compartment is skewed towards central memory CD8 T cells, whereas adult human memory T cells are dominated by effector memory T cells. The murine memory compartment is akin to that of neonate humans, suggesting there are factors missing in SPF mice that are required to mature the T cell compartment. We wanted to ask how pathogen exposure changes the memory compartment of mice, so we utilized a model of pet shop mouse co-housing (COH), which exposes mice to a wide variety of normal mouse pathogens. COH mice display a substantial increase in long-lived effector CD8 T cells (LLEC). LLEC are a CD8 T cell memory population described by the Hamilton Lab that is phenotypically more effector-like and are highly effective at clearing systemic infections when compared to other memory T cells. However, LLEC display reduced homeostatic and antigen-driven proliferation in SPF mice leading to a lower representation in the memory pool. The factors in COH that support LLEC expansion and persistence are currently unknown, and it is also unclear if COH impacts LLEC function. Thus, the goal of this study is to understand what intrinsic and environmental factors contribute to LLEC formation and maintenance, as well as determine how LLEC function contributes to memory responses in COH mice. I have found that COH LLEC are more polyfunctional compared to SPF LLEC, and my preliminary work has found that LLEC turnover is increased in COH mice. Future studies will determine what specific inflammatory cues lead to LLEC expansion, and if this process can be altered to improve T cell responses to infection and vaccination.
Supported by grants from the NIH (R01 AI155468)
The role of GPR132 in regulating T cell function
Authors: Tovar Giuseppina Marchesini , Bergsbaken Tessa 
Published: August 2023

Abstract
CD8+ T cells are vital in controlling pathogens and undergo robust expansion upon priming. Tissue-resident memory T cells (Trm) that reside in non-lymphoid tissues are less responsive in terms of expansion; however, the signals within the tissue that direct the quantity and quality of CD8+ Trm pools are still unclear. G protein coupled receptors (GPCRs) sense and integrate environmental signals and are essential for regulating T cell function. GPR132 or G2A modulates homeostasis in mature peripheral T cells, and Gpr132−/− mice develop an autoimmune syndrome accompanied by expansion of the T cell compartment. GPR132 ligands are synthesized by intestinal epithelial cells and commensal bacteria, making GPR132 a potential target for regulating T cell expansion in the intestinal tissue. We investigated the function of GPR132 during intestinal infection by Y. pseudotuberculosis.GPR132 expression was elevated on T cells early after infection . Gpr132−/− cells displayed enhanced expansion, outnumbering wild-type (WT) cells by 3–4 fold in all tissues. Early differentiation was not impacted by GPR132-deficiency, as there were no differences in circulating and Trm memory precursor subpopulations between WT and Gpr132−/− cells. To dissect the mechanism of GPR132 action, we examined the transcriptome of WT and Gpr132−/− naïve T cells. Minimal differences in gene expression were observed, and both showed comparable proliferation upon TCR-engagement in vitro. These data suggest enhanced responsiveness of Gpr132−/−T cells was not programmed at the naïve stage but develops during T cell activation. Our results expose a role for GPR132 signaling axis in regulating T cell immunity and demonstrate GPCRs can be targeted to modulate T cell responses.
New Jersey Commission on Cancer Research Predoctoral Fellowship Grant COCR23PRF011.
Sublethal whole-body irradiation induces permanent loss and dysfunction in pre-existing pathogen-specific memory CD8 T cell populations
Authors: Heidarian Mohammad , Jensen Isaac J , Hassert Mariah , Kannan Shravan Kumar , Xue Hai-Hui , Harty John T , Badovinac Vladimir P 
Published: August 2023

Abstract
The increasing use of nuclear energy sources inevitably increases the risk of accidental or deliberate radiation-exposure. However, the extent to which radiation-exposure impacts memory CD8 T cells, potent mediators of immunity to recurring intracellular infections and malignancies, remains understudied. Using P14 LCMV immune chimeric mice (P14 chimeras), we observed that sublethal (5Gy) whole body irradiation (WBI) induced a rapid decline in the number of naive (TN) and P14 circulatory memory CD8 T cells (TCIRCM) with the former being more susceptible to radiation-induced death. While TN cell numbers rapidly recovered, the number of P14 TCIRCM cells remained low at least nine months after radiation-exposure. Additionally, the remaining P14 TCIRCM in irradiated hosts exhibited an inefficient transition to a central memory (CD62Lhi) phenotype compared to non-irradiated P14 chimeras. WBI also resulted in long-lasting T-cell intrinsic deficits including diminished cytokine and chemokine production in response to antigen-stimulation along with impaired secondary expansion upon cognate Ag re-encounter. Irradiated P14 chimeras displayed significantly higher bacterial burden after challenge with L. monocytogenes expressing GP33 compared with the non-irradiated controls, likely due to radiation-induced numerical and functional impairments. Taken together, our findings suggest that sublethal radiation-exposure caused long-term numerical decline, impaired differentiation, and functional dysregulation in pre-existing TCIRCM, which rendered previously-protected hosts susceptible to re-infections.
Supported by NIH Grants GM134880, AI114543, The Holden Comprehensive Cancer Center at The University of Iowa and its National Cancer Institute Award P30CA086862
Deciphering molecular and functional codes of human memory lymphocytes
Authors: Singh Amit K , Roy Roshni , Kaileh Mary , Sarantopoulou Dimitra , Hernandez Dena , Arepalli Sampath , Bektas Arsun , Kim Jaekwan , McKelevy Julia , Zukley Linda , Dunn Christopher , Nguyen Cuong , Wallace Tonya , Wood William , Piao Yulan , De Supriyo K , Sen Jyoti Misra , Weng Nan-ping , Ferrucci Luigi , Sen Ranjan 
Published: August 2023

Abstract
Long-term immunity against infections and effective response to vaccination are dependent on unique feature of lymphocytes referred as “memory generation”. Majority of our understanding is established on murine data and our understanding of human naive to memory differentiation is limited. In our ongoing study we explored epigenetics (DNA methylation and accessible chromatin), transcriptomics (basal, activation and proliferation induced gene expression), intracellular cytokine assay (high-parameter flow cytometry) of naive and memory B and T lymphocytes subsets from the healthy donors. We explored the epigenetic changes associated with memory differentiation. However, relationship between epigenetics and transcriptomic outcomes didn’t explain entirely the properties of being memory or naïve lymphocyte. To understand mechanistic differences, naive and memory cells of B and CD4 T lymphocytes were activated in vitro using either antigen receptor (BCR or TCR crosslinking with antibodies) or PMA+Ionomycin (pan-activation) and assayed for early or late gene expression and for intracellular cytokine profiles. Surprisingly, majority of transcriptomic patterns were similar between naive and memory lymphocytes while their cytokine expression profiles were significantly different. These findings indicate the significant role of translational machinery influencing the memory and naïve lymphocyte functions. Our results are in direction of segregating transcription and translation mediated dependencies of adaptive memory. These findings will provide the foundation for future studies related to dysregulation of memory cell differentiation and function in aging and infections.
This project was entirely supported by intramural funding of NIA-NIH.
Transcription factor Nfil3 is a regulator of CD8 T cell differentiation in mouse Influenza A infection
Authors: Sportiello Michael John , Topham David J 
Published: August 2023

Abstract
After an acute respiratory infection is cleared, most T cells that controlled the infection die off. Tissue resident memory CD8 T cells (TRM) remain in the lung, poised to fight off a recurrent infection. These TRM have large impacts on the survival and morbidity of subsequent infection. While many have studied this subset to understand what causes differentiation into this essential T cell subset, a master regulator of this phenotype remains elusive. To these ends, RNA and ATAC sequencing experiments of TRM were conducted after viral clearance to investigate the existence of a master regulator. Transcription factor Nfil3 became a likely candidate after integrated omics analyses. Flow cytometry to fully characterize the levels of Nfil3 in all T cell subsets of the lung, spleen, and draining lymph node was conducted 7, 14, and 43 days post infection (dpi). At days 7 and 14 dpi, Nfil3 correlated with pre-TRM markers. At 43 dpi, Nfil3 was highest in TRM and lowest in central memory T cells. Finally, experiments were performed to investigate if Nfil3 played a causal role in TRM development or maintenance. T cells were transduced with Nfil3 overexpression constructs and adoptively transferred into mice, which were then infected. Notable changes in differentiation were observed between treatment and control. T cell proliferation was also affected ex vivo in a proliferation dye assay, implying that Nfil3 plays a role in the acute response. Finally, using a CD8-specific inducible floxout system, Nfil3 was floxed out during acute infection, recently post viral-clearance, and 6 weeks after during the memory phase to appreciate the effect on T cell differentiation. Overall, we argue Nfil3 plays a role in CD8 T cell differentiation in respiratory infections.
This work was funded by a Program Project grant through the National Institutes of Health, National Institute of Allergy and Infectious Diseases P01-AI102851 and through the National Institutes of Health training grant T32GM007356-46 and the National Institutes of Health training grant T32HL066988-20.
The majority of circulating human B cells belong to a naïve anergic B cell subset distinguished by expression of CD73
Authors: Dizon Brian , Pierce Susan 
Published: August 2023

Abstract
In humans, it is estimated that ~40% of peripheral blood (PB) naïve (CD19+ CD27− CD45RBMEM− CD38−) B cells are in a state of anergy defined as IgD+ IgMlow. Presumably these anergic B cells express only weakly autoreactive B cell receptors (BCR) that allowed them to escape elimination by central tolerance mechanisms in the bone marrow, but were sufficient to induce anergy in the periphery. Although the ultimate fate of these B cells is not known, it is hypothesized that anergic B cells undergo a process of redemption in which they are activated and somatically hypermutate away from self, allowing them to be recruited into foreign antigen-specific responses. To better characterize human anergic B cells, we utilized a panel of 18 antibodies specific for B cell surface markers and BCR isotypes, which allowed identification of the known human B cell subsets by flow cytometry. We determined that ~50% of B cells were contained in the naïve compartment, of which ~60% were anergic (IgD+ IgMlow) cells distinguished by the expression of CD73. In contrast, CD11c+ CD27− B cells (termed ABCs) and CD45RB+ CD27− MBCs comprised only 0.6% and 7.0% of circulating anergic B cells, respectively. Using 9G4 to identify inherently autoreactive B cells expressing germline VH4–34, we found that the majority of 9G4+ cells were naïve anergic B cells that express CD73. Thus, in humans the CD73+ naïve compartment appears to be the major reservoir of anergic B cells, possibly for redemption and participation in immune responses to pathogens. Studies are underway to define the responses of these B cells in health and disease.
This work was supported by the Intramural Research Program of the US National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Neutrophils show distinct patterns of activation in the context of infection with different pathogens
Authors: Chen Fei , Espinosa Vanessa , Wu Wenhui , Peignier Adeline , Wang Keyi , Lothstein Katherine , Rivera Amariliz , Parker Dane , Gause William C 
Published: August 2023

Abstract
Alternatively activated neutrophils (N2) enhance lung anti-helminth trained macrophage effector function in response to infection with the helminth Nippostrongylus. brasiliensis (Nb) (Fei Chen, et al., NI, 2014, CR, 2022). However, potential differences in activation patterns of neutrophils with different pathogens is not yet well studied. We report here lung neutrophils bear unique gene expression profiles at 2 days after infection with Nb, fungi (Aspergillosis fumigatus (Af)), and bacteria (Staphylococcus aureus (SA). AF and SA triggered genes associated with cell death and autophagy but differed greatly in metabolic activity. In contrast, Nb induced gene expression patterns characteristic of type 2 immunity, xenobiotic pathways, and cell proliferation. Further analysis revealed increased edu incorporation, KI-67 and IL-13 expression in neutrophils in the lung but not in the blood and bone marrow. Furthermore, the proliferating neutrophil subset predominantly expressed IL-13 and was IL-4R dependent. To directly examine neutrophils proliferating in the lung after Nb infection, Nb-primed neutrophils (CD45.2) were transferred to CD45.1 Nb inoculated recipients. At day 10 after inoculation, donor neutrophils were readily detected and were proliferating as measured by ki-67 staining and edu incorporation. These studies suggest that neutrophils exhibit distinct activation states following infection with different pathogens. Unlike neutrophils typically associated with microbial infection, where rapid turnover from cell death typically occurs, neutrophils activated following Nb infection persist and undergo cell cycling within the remodeled lung tissue microenvironment.
Plasmodium falciparum mRNA liver stage antigens induce antibody and liver CD8 TRM and CD8 TE cell responses in mice
Authors: Tan Steven , Alameh Mohamad-Gabriel , Renn Jonathan P , Allen Joselyn Natasha , Pichugin Alexander V , Duffy Patrick E , Weissman Drew , Krzych Urszula 
Published: August 2023

Abstract
Plasmodium spp. cause more than half a million malaria deaths annually and the only approved vaccine, RTS,S, based on P.falciparum (Pf) circumsporozoite protein (CSP), confers incomplete and non-durable protection. A strategy to improve malaria vaccines involves combining Ags of different Plasmodium stages such as sporozoite (spz) and liver stage (LS). This strategy promises a broader repertoire of specific antibodies (Ab), CD4 and CD8 T cells. We have shown that mice immunized with a combination of P. berghei (Pb) CSP and LS Ags expressed as DNA-Adenovirus generate higher protection than CSP alone. Protection is associated with Ag-specific Abs and liver CD8 TRM cells. We hypothesized that spz that escaped CSP-specific Abs were targeted by LS-Ag-specific responses. Our current efforts are directed towards utilizing mRNA template as it can accommodate many Ags. We designed mRNA-LNP expressing single Pf-LS Ags, 305w and SHMT, based on protective rodent parasite LS Ag orthologues, for immunization of mice. Analyses of mRNA-Pf-305w- and Pf-SHMT-induced immune responses show a divergence of reactivities. Whereas Pf-305w induced high Ab titers, Pf-SHMT induced liver CD8 TRM and CD8 TE cells that exceeded Pf-305w-induced CD8 T cells. Peptides corresponding to Pf-SHMT recalled high IFN-g responses, a signature of protective immunity. We continue to characterize and evaluate contributions of T cell and B cell responses induced with combinations of Pf-LS Ags including Pf-CSP to protective immunity against transgenic parasites. mRNA vaccines provide a rapid, flexible platform to explore malaria vaccine improvements where liver CD8 TRM and CD8 TE cells, B cells and Abs may be crucial for highly efficacious and protracted protection.
Natural antibodies mediate resistance to Acinetobacter baumannii respiratory infections
Authors: Wilson Timothy James , Islam Aminul A , Actis Luis A 
Published: August 2023

Abstract
Acinetobacter baumannii is a growing public health threat due to increasing incidence of carbapenem-resistant strains in U.S. hospitals. With widespread antibiotic resistance, there is an urgent need for alternative therapies to treat these infections, which are often acquired in hospital intensive care units. Antibody-based immunotherapies offer one potential treatment avenue, however, adaptive immune responses to A. baumannii have not been well characterized. Pilot experiments, using a mouse pneumonia model to explore the role of adaptive immunity in clearing A. baumannii, uncovered an unexpected and severe defect in resistance to A. baumannii infection in Rag2−/− mice during the first 48 hours after infection. Subsequent experiments showed that intranasally infected Rag2−/− or B cell-deficient μMT mice are impaired compared to wild type mice in clearing bacteria from lung, liver, and spleen at 24 hours post infection. Prophylactic administration of normal mouse serum or purified immunoglobulins from naive mice demonstrates a protective effect of natural antibodies (NAbs) by rescuing Rag2−/− mice from severe infection. Analysis of C3 complement protein binding demonstrated that NAbs increased C3 protein deposition on A. baumannii cells, indicating the activation of the classical complement pathway as a potential mechanism of action. Overall, our study demonstrates a previously unknown role for natural antibodies in the innate resistance to Acinetobacter pneumonia, a finding that may lead to the development of effective therapies against human infections caused by this antibiotic-resistant pathogen.