bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing a “critical window” of immune development: how perturbation of developmental hematopoiesis shapes immune function and susceptibility to disease in offspring
Authors: Beaudin Anna E , Lopez Diego A , Apostol April , Hernandez Gloria E , Forsberg Camilla 
Published: January 2023

Abstract
During development, fetal hematopoietic stem cells (HSCs) are responsible for the production of “unconventional” innate-like immune cells that persist across the lifespan and contribute to adult immunity. Dysregulation of fetal-derived immune cells contributes to pathogenesis in a variety of immune tolerance disorders, including allergy and asthma; however, the cellular and molecular mechanisms driving pathogenesis are unknown. Using a fate-mapping approach, we have previously identified a developmentally-restricted HSC (drHSC) that is lymphoidbiased and specifically gives rise to innate-like lymphocytes. The drHSC exists during perinatal development but disappears postnatally and does not persist into adulthood under homeostatic conditions. Our discovery of a transient cell-of-origin for a specialized component of adult immunity defines a “critical window” of immune development, during which phenotype can be shaped by extrinsic inputs in early life. We have validated the existence of this critical window of immune development by demonstrating that maternal immune perturbation with a single low-dose injection of poly(I:C) at mid-gestation induces lasting changes to the both hematopoiesis and immunity in offspring. Specifically, maternal immune perturbation causes expansion of the drHSC population in offspring and its inappropriate persistence into adulthood. Furthermore, inappropriate expansion and persistence of the drHSC population consequently results in parallel expansion of innate-like lymphocytes, thereby altering immune landscape and function in offspring. Ongoing work investigates the consequences of developmental perturbation on susceptibility to immune dysfunction, including asthma.
Plasma cells are obligate enhancers of age-associated myeloid skewing
Authors: Pioli Peter , Casero David , Montecino-Rodriguez Encarnacion , Morrison Sherie L , Dorshkind Kenneth A 
Published: January 2023

Abstract
In humans and mice, aging results in significantly elevated myelopoiesis and the increased production of inflammatory cytokines with age is thought to underlie this phenomenon. The observation that treatment of young mice with factors such as interleukin (IL)-1 can skew hematopoiesis towards myeloid development is consistent with this hypothesis. However, the cellular source(s) of inflammatory cytokines in the aging bone marrow has not been fully defined. We observed that plasma cells (PCs) accumulate in the bone marrow with age and acquire an inflammatory gene signature. Furthermore, we observed that their depletion in vivo using anti-CD138 antibodies resulted in a significant decline in myelopoiesis as demonstrated by a reduction in the number of myeloid biased hematopoietic stem cells, myeloid progenitors and mature myeloid cells. We also found that anti-CD138 treated mice exhibited reduced expression of genes encoding inflammatory cytokines in bone marrow stromal cells, indicating that plasma cells can regulate inflammatory cytokine production by other microenvironmental components. We tested whether this inflammatory network was necessary to drive age-associated myeloid skewing by treating old mice with Anakinra or Enbrel to abrogate IL-1 and tumor necrosis factor alpha (TNF-α) signaling, respectively. Concurrent blockade of both signaling pathways in old mice resulted in the significant reduction of bone marrow myelopoiesis, which was not observed upon inhibition of either pathway alone. These data demonstrate a previously unappreciated ability of inflammatory PCs to stimulate myelopoiesis and implicate them at the center of an inflammatory regulatory network in the aging bone marrow.
Merocytic dendritic cell: a new subset of conventional dendritic cells
Authors: Audiger Cindy , Lesage Sylvie 
Published: January 2023

Abstract
Conventional dendritic cells (cDC) are potent antigen-presenting cells that induce the activation of naïve T cells in response to pathogens. cDC activity is mediated primarily by two cDC subsets, namely cDC1 and cDC2, each bearing unique properties. Recently, another DC subset, termed merocytic dendritic cells (mcDC), was defined. In contrast to both cDC1 and cDC2, mcDC are able to reverse T cell anergy, even in non-inflammatory conditions, properties that could be exploited to potentiate cancer treatments. Here, we further characterize mcDC to determine their relationship to cDCs. First, we demonstrate that mcDC express key cDC traits, namely they express the cDC-restricted transcription factor, Zbtb46, and are very potent inducers of mixed lymphocyte reactions. Second, transcriptomic studies reveal that mcDC are more closely related to cDC1 than to cDC2. In contrast, similar to cDC2, mcDC are dependent on IRF4, but not IRF8 and BATF3, two major transcription factors required for cDC1 differentiation. Third, investigating mcDC population dynamics in reconstitution kinetics studies and in parabiotic mice, we demonstrate that, as for cDC1 and cDC2, mcDCs are terminally differentiated cells. Altogether, these data demonstrate that mcDC compose novel cDC subset. Defining the properties of mcDC in mice may help identify a functionally equivalent subset in humans leading to the development of novel cancer immunotherapies.
Isthmin 1 identifies a subset of lung hematopoietic stem cells and it is associated with systemic inflammation
Authors: Rivera-Torruco Guadalupe , Mendiola Carolina Abigail , Floriano Tania Angeles , Franco Rafael , Parra-Ortega Israel , Vilchis Armando , Maravillas-Montero José Luis , García-Contreras Rodolfo , Contreras Oscar Medina , Nava Porfirio , Ortiz-Navarrete Vianney , Licona-Limon Paula , Valle-Rios Ricardo 
Published: January 2023

Abstract
Hematopoiesis is a highly regulated process and it’s widely described in bone marrow, the classical niche for hematopoietic stem cells (HSCs). The lungs are a novel niche of HSCs, as recently described by Lefrançais in 2017, however, little is known about the nature of these cells. Isthmin 1 (ISM1) is a secreted molecule important in developmental hematopoiesis in zebrafish; moreover, it is known that murine lungs express high levels of ISM1 and its secretion is altered after LPS challenge. In this work we performed multiparametric flow cytometry identifying a subpopulation of lung-resident HSCs expressing ISM1. Then we wanted to assess if HSCs ISM1+ cells are affected under inflammatory insults. Acute infection in mice with Pseudomonas aeruginosa showed that lung-derived HSCs ISM1+ are increased, indicating that the lung-HSCs are perturbed. Due to our model produced systemic inflammation we sought to investigate whether circulating ISM1+ cells were affected, we found that the percentage and absolute numbers of ISM1+ cells in blood were slightly diminished. Since ISM1 is a secreted molecule we evaluated its plasmatic levels by ELISA. We discovered a reduction in ISM1 plasmatic levels during murine sepsis with Pseudomonas aeruginosa. Then, we sought to analyze ISM1 levels in human inflammation; we retrieved samples from pediatric individuals with sepsis and adult patients with 2th and 3th grade burn injuries, and in both cases, we detected reduced levels of plasmatic ISM1. Our data suggest that ISM1 is likely a regulator of hematopoiesis in the lung but also may have a function in the regulation of systemic inflammation in mice and humans. We suggest that ISM1 is a novel biomarker of systemic inflammation.
Identification of splenic progenitors for CD11b high myeloid cells in the long-term culture with GM-CSF
Authors: Ryu Seul Hye , Na Hye Young , Sohn Moah , Choi Wanho , In Hyunju , Shin Hyun soo , Park Ji Soo , Park Chae Gyu 
Published: January 2023

Abstract
Granulocyte macrophage-colony stimulating factor (GM-CSF) is a key hematopoietic cytokine for the development of immune cells from progenitors in bone marrow (BM). However, the role of GM-CSF in hematopoiesis outside of BM has been less well understood. In a recent report, we discovered that significant proliferation of CD11bhi myeloid cells, including CD11chi dendritic cells (DCs) and CD11clo macrophages, were detected in the culture of splenocytes with GM-CSF between 1 and 3 weeks. To further characterize this slow myelopoiesis of CD11bhi cells in vitro, we set out to find their progenitors in spleen. We have identified and isolated the distinct splenic populations of myeloid progenitors based on the established cell-surface markers of hematopoietic progenitors in BM. When those isolated splenic progenitors were cultured with GM-CSF, lineage− CD117+CD115−CD16/32+ splenic cells were effective to produce CD11bhi myeloid cells. Our current study indicates that splenic progenitors comparable to BM granulocyte-macrophage progenitor (GMP) are responsible for generating CD11bhi DCs and macrophages in the long-term culture with GM-CSF.
Acute and chronic waves of myeloid cell maturation and myelopoiesis with high fat diet
Authors: Bowers Emily , Abrishami Simin , Singer Durga 
Published: January 2023

Abstract
Diet-induced obesity is associated with an infiltration of monocytes into the adipose tissue in male mouse models. These monocytes differentiate into inflammatory macrophages that drive insulin resistance. This increase in circulating monocytes originates in the bone marrow (BM) where hematopoietic stem cells (HSC) and myeloid-restricted progenitors (GMPs and PreGMs) expand. HSCs isolated from BM of male mice on high-fat diet (HFD) for 16 weeks show myeloid lineage skewing that lasts through successive bone marrow transplants (BMT). This suggests that HFD induces changes to the HSC niche - a multicellular structure that produces regulatory signals that are critical for maintaining the HSC pool. While BM adipocytes expand with HFD exposure, the niche cells promoting myelopoiesis with HFD are unknown. We chose to investigate two cell populations that have been implicated in driving myelopoiesis in other conditions; the BM endothelial cell (BMEC), a critical HSC niche cell, and neutrophils. We hypothesize that HFD induces HSC expansion and reprogramming through neutrophil-BMEC communication. Using 60% HFD in C57Bl/6J mice we evaluated circulating and BM neutrophils and Ly6C monocytes; HSCs and progenitors, and BMECs during short- and long-term HFD exposure. We found that as early as 24 hours after mice went on HFD there is a significant spike in circulating mature neutrophils that return to normal levels by 72 hours only to expand again by 16 weeks HFD. Ly6Chi monocytes rose only after 1 month of HFD exposure. BMECs do not appear to be altered in number with HFD in short- or long-term assays. Further qualitative analysis of BMECs, MAT, and neutrophils are necessary to determine which cells are critical for regulating the HSC niche in HFD.
OPN receptor expression on immune effector cells in RSV infection is regulated by NKT cells
Authors: Qureshi Mahboob Hossain , Qureshi Omar , Durre Kainath 
Published: January 2023

Abstract
RSV infection in early life predisposes to asthma later in life. Role of aberrant immune responses to childhood viral infections is well documented. Involvement of myeloid (mDC) and plasmacytoid (pDC) Dendritic Cells (DC) and Natural Killer T-cells (NKT) has been reported. Osteopontin (OPN) modulates the immune responses to viral infections. The current studies looked into the role of NKT cells in regulating the OPN receptor expression in RSV infection on DC, T and B cells, which will elucidate the role of OPN in preventing RSV-induced hyper-reactive airway and asthma. Five-day-old BALB/C and NKT−/−(CD1d−/−) mice were infected intranasally with RSV; and expression of OPN receptors (CD44 and CD51/61) were examined at designated post-infection days on lung mDC (CD11blo/−CD11chiCD45Rlo/−), pDC (CD11blo/−CD11clo/−CD45Rhi), T (CD3+) and B (CD19+) cells by flow cytometry. Expression of CD44 and CD51/61 were decreased on mDC, pDC, T and B cells in RSV infected wild pups compared to the control pups. On the other hand, OPN receptor expression was enhanced in the RSV-infected NKT−/− pups compared to the infected wild pups and uninfected NKT−/− pups suggesting a regulatory role of NKT cells on expression of OPN receptors, as RSV-infected NKT−/− pups had significantly increased CD44 and CD51/CD61 expression on DC and lymphocytes. Thus, decreased OPN receptor expression during RSV infection very likely diminishes the action of endogenous OPN allowing skewed polarization of DC and subsequent T cell responses. Therefore, abolishing the action of NKT cells to augment the action of endogenous OPN; and/or administration of exogenous OPN warrant further investigation as a new therapeutic strategy against RSV-associated asthma.
The Ikaros zinc finger transcription factor Eos regulates CD4+ TH1 and CD8+ TC1 differentiation programs
Authors: Sreekumar Bharath Krishnan Nair , Powell Micheal Duane , Read Kaitlin , Zafar Jawad , Jones Devin , Baker Chandra , Allen Irving C , Oestreich Kenneth J. 
Published: January 2023

Abstract
CD4+ T helper 1 (TH1) cells are essential mediators of immune responses directed against viruses and intracellular bacteria. As such, elucidation of the regulatory mechanisms underlying their development and function is necessary to direct the function of these cells in immunotherapeutic approaches to treat human disease. Recently, we demonstrated that the Ikaros zinc finger (IkZF) factor Aiolos cooperates with STAT3 to induce Bcl-6 expression in CD4+ T follicular helper (TFH) cells. Given conservation between individual members of the IkZF and STAT families, we hypothesized that additional IkZF/STAT complexes may regulate the development of other T cell subsets. Indeed, we find that the expression of the IkZF factor Eos is elevated in TH1 cells compared to TFH and naive CD4+ T cell subsets. We further find that induction of Eos expression is dependent on IL-2 signaling and is mediated, in part, by STAT5. Furthermore, expression of TH1 markers, including Blimp-1, IL-2rα, and IL-2rβ, as well as the production of the TH1-associated cytokine, IFN-γ were significantly diminished in Eos-deficient TH1 cells. Mechanistically, we found that Eos physically interacts with STAT5 and that these factors are co-enriched at the Prdm1 and Il2ra gene loci in TH1 cells. Intriguingly, we also found that Eos-deficient CD8+ cells differentiated under TC1-polarizing conditions displayed reduced expression of the TC1 genes encoding T-bet, Blimp-1, IFN-γ, and Granzyme B. Collectively, our data support a conserved role for a regulatory axis involving IL-2, STAT5, and Eos that drives the differentiation and function of CD4+ TH1 and CD8+ TC1 cells.
Adventitial stromal cells define group 2 innate lymphoid cell tissue niches
Authors: Molofsky Ari B , Dahlgren Madelene W , Jones Stephen W , Dubinin Alexandra , Farhat Sepideh , Ortiz-Carpena Jorge F , Yu Kevin S , Lee Katharine , Wang Chaoqun , Molofsky Anna Victoria R , Tward Aaron D , Krummel Matthew F , Peng Tien 
Published: January 2023

Abstract
Mobilization of type 2 immune responses is critical to both physiologic tissue remodeling and allergic pathology such as allergic asthma. However, whether there are physical tissue niches with unique cellular constituents that mediate type 2 immunity is unknown. We used quantitative 3D-imaging to define tissue niches of group 2 innate lymphoid cells (ILC2), critical instigators of type 2 immunity. We identified a dominant adventitial ‘cuff’ niche around vessels, airways, and ducts, present in the lung and multiple other tissues. ILC2s, as well as subsets of other tissue-resident hematopoietic cells, localized to these sites. However, ILC2s were most intimately associated with fibroblast-like adventitial stromal cells (ASCs) that were functionally distinct and sufficient to support ILC2 survival and activation. Here we discuss data supporting a model where ILC2s engage in a conversation with micro-anatomically and functionally distinct adventitial mesenchymal cells and other niche components, creating dynamic type 2-biased tissue foci that regulate tissue allergic immunity.
Noncanonical NF-κB controls stem cell signatures in the colonic mucosa and affects susceptibility to inflammation-induced carcinogenesis
Authors: Allen Irving C , Eden Kristin , Morrison Holly , Rothschild Daniel , Brown Stephan , Holl Eda 
Published: January 2023

Abstract
NF-κB signaling is divided into two distinct pathways, defined as either canonical or noncanonical. Canonical NF-κB signaling is well described and characterized. However, significantly less is known regarding mechanisms regulated by the noncanonical NF-κB pathway, especially outside of the lymphoid system. Recently, interest in the role of noncanonical NF-κB in the mucosal immune system has been increasing, with emphasis on NF-κB inducing kinase (NIK). NIK is an essential kinase in this cascade. Our data shows that lack of noncanonical signaling through the complete knockout of Nik in mice results in an aberrant large intestine phenotype characterized by reduced stem cell marker expression, altered regeneration and differentiation capacity under stress, changes in the microbiome, and predisposition to inflammation-associated tumorigenesis. Subsequent mechanistic studies utilizing novel mice with cell type specific deletions of either RelA/p65 or Nik revealed separate and distinct rolls for canonical and noncanonical NF-κB signaling in attenuating inflammation and tumor progression. RelA/p65 attenuates disease progression through the myeloid compartment in the gut, whereas Nik functions through the intestinal epithelial cell compartment. Dysregulation of noncanonical signaling is also observed in human colorectal cancer patients, which have marked suppression of this pathway in colonic biopsy samples. Together, these findings indicate that noncanonical NF-κB signaling is a critical regulator of immune system homeostasis in the gastrointestinal tract and plays a vital protective role against colorectal cancer.
Intestinal Goblet cells and Goblet Cell Associated Antigen Passages regulate the balance between Tregs and Th17
Authors: Kulkarni Devesha Hrishikesh , Gustafsson Jenny , Davis Jazmyne , McDonald Keely , Hsieh Chyi , Newberry Rodney D 
Published: January 2023

Abstract
Tolerance towards dietary antigens and luminal microbes is essential to maintain homeostasis, the breakdown of which results in development of inflammatory bowel disease (IBD). T-helper 17 (Th17) and T-regulatory (Treg) cells are abundant in the intestinal mucosa, where they function to protect the host from pathogens and to restrain excessive effector T-cell responses, respectively. How the balance and switch between Treg and Th17 responses is maintained in the steady state to promote tolerance and how this balance becomes altered to favor Th17 responses in the setting of IBD is not known. We have identified that intestinal goblet cell (GC) associated antigen passages (GAPs), are a major pathway for steady-state luminal antigen transfer to lamina propria - dendritic cells (LP-DCs). In addition, GAPs are necessary for the imprinting of LP-DCs with tolerogenic properties, for the de novo induction of Tregs specific for dietary antigens, and the maintenance of pre-existing LP Tregs. Moreover, GAP inhibition results in the expansion of Th17 cells in the small intestine LP. Consistent with this, single cell profiling of intestinal lymphocytes revealed enhanced Th17 pathway gene signatures in mice lacking GCs. These observations strongly support that GCs/GAPs have a previously unappreciated role in maintaining the functional balance between Treg and Th17 cell.
Dissecting the tissue-specific mechanisms that support the maintenance of intestinal regulatory T cells
Authors: Morales Elisa Cruz , Hart Andrew P. , Laufer Terri M. 
Published: January 2023

Abstract
Intestinal regulatory T cells (Tregs) are important to maintain tolerance toward food antigens (Ag) and commensals. Understanding the mechanisms for localization and maintenance of intestinal Tregs will help to identify novel immunotherapies for inflammatory intestinal diseases.
Previously we used K14 transgenic mice lacking peripheral TCR-MHCII interactions to show that the small intestine lamina propria (siLP) is a niche for Tregs that can be filled and maintained independently of Ag-specific signals. Now, we have begun to dissect the interactions that sustain these MHCII-independent siLP Tregs.
Tregs can be phenotypically and functionally divided into central and effector Tregs. Central Tregs preferentially migrate from thymus toward secondary lymphoid tissues. Effector Tregs reside mainly in non-lymphoid tissues and acquire a tissue-specific phenotype. Although it has been proposed that Ag-specific signals mediate effector Treg differentiation, we find that siLP Tregs acquire an effector phenotype independently of local MHCII. Instead, CTLA4/CD28—but not ICOS—engagement is important to sustain proliferation of MHCII-independent siLP Tregs. These results suggest that, in the absence of MHCII-TCR stimulation (Signal 1), costimulatory pathways (Signal 2) are still important to maintain Tregs in the intestine.
Finally, we find that siLP Tregs localize in two distinct anatomical compartments: randomly within villi and aggregated in organized lymphoid structures known as isolated lymphoid follicles.
Our results show that the intestinal niche can sustain a population of effector Tregs independently of Ag-specific signals but via costimulatory signals like CTLA4/CD28.
Indiscriminate nature of lung resident CD8+ TRM cells reactivation and their varied reactivation profiles
Authors: LOW JUN SIONG , Amezcua Caro , Sefik Esen , Harman Christian C.D. , Jackson Ruaidhri , Jiang Xiaodong , Kelly Joseph Barrack , Cauley Linda S , Flavell Richard A , Kaech Susan 
Published: January 2023

Abstract
CD8+ tissue resident memory (TRM) cells are poised at the portals of infection and confer immediate protection upon reinfection. Despite the critical role of CD8+ TRM cells in long-term protective immunity, the precise mechanics governing their reactivation in-situ are unclear. Seminal work by Leo Lefrançois' group showed that circulating (TCIRC) memory CD8+ T cell depends on CD11c+ antigen-presenting cells (APCs) for reactivation, however, TRM cells are reactivated within peripheral tissues, raising the question of whether the same principle is conserved. We examined this question, focusing on influenza infection, because APCs in the lung are well-defined and lung-resident TRM cells are critical for heterologous immunity to influenza. Using a TCR transgenic Nur77 reporter to delineate TCR-specific from bystander activation in CD8+ TRM cells, we characterized the superior reactivation kinetics in CD8+ TRM cell compared to CD8+ TCIRC. We also identified unique TCR-specific signatures and bystander-specific signatures in the kinetics of CD8+ TRM cells and TCIRC cells reactivation respectively. While we observed the strict requirement for CD11c+APCs in TCR-driven CD8+ TCIRC reactivation, CD8+ TRM cells exhibit promiscuity in their interactions with antigen-presenting partners in that they can be reactivated by both hematopoetic and non-hematopoetic cells. This study explains how the anatomical location of CD8+ TRM cells can confer unique advantage by demonstrating their superior reactivation kinetics and the indiscriminate nature of CD8+ TRM cell reactivation as well as showcasing the transcription profiles of TRM and TCIRC cells following different modes of activation.