bluuebunny/crossref_metadata_2025_split huggingface dataset:
Missing KIR ligand in the host-versus-graft (HvG) direction is associated with second cell infusion in children with NK+ severe combined immunodeficiency (SCID) receiving hematopoietic stem cell transplantation.
Authors: Wahlstrom Justin , Bender Henry , Yin Ziyan , Logan Brent , Rajalingam Raja , Dvorak Christopher C. , Haddad Elie , Cowan Morton J 
Published: January 2023

Abstract
Functional NK cells are thought to mediate graft rejection in allogeneic hematopoietic stem cell transplantation (HSCT) for SCID. We hypothesized that missing KIR ligand (MKL) in the HvG direction mediates NK alloreactivity and is associated with increased rates of 2nd cell infusion requirement in NK+ SCID patients treated with HSCT.
Data collected by the Pediatric Immune Deficiency Treatment Consortium (PIDTC) from 1982 to 2012 were reviewed. A total of 174 NK+ SCID transplant recipients were identified. Of these, HLA-B typing was available for 172 recipient/donor pairs, and HLA-C typing was available for 131 pairs. MKL was identified if Bw4, C1, or C2 inhibitory ligands were present in the recipient but not the donor.
MKL was identified for Bw4 in 18 of 172 donors; for C1 in 11 of 131 donors; and for C2 in 9 of 131 donors. Combined Bw4, C1, and C2 MKL analysis was feasible for 129 transplants; 38 of these donors were missing one or two ligands in the HvG direction. Missing Bw4 ligand alone was not associated with decreased EFS or increased need for 2nd cell infusion. The incidence of 2nd infusion at 2 years was significantly lower for pairs without missing HLA-B or HLA-C ligands (19.3%, 95% CI 11.8% – 28.2%) compared to those with MKL (28.9%, 95% CI 15.5% – 43.9%; Gray’s p=0.04). EFS was 63.2% in patients with MKL (95% CI 45.9% – 76.3%) and 75.2% in those without MKL (95% CI 64.7% – 82.9%; Gray’s p=0.05).
Missing KIR ligand in the HvG direction is associated with 2nd cell infusion in HSCT for NK+ SCID and may represent a mechanism for NK alloreactivity in this setting. Multivariate analysis and biologic studies of NK reactivity in SCID patients are needed to better understand the role of recipient NK cells in HSCT.
Deletion of AMP-activated protein kinase (AMPK) in donor T cells mitigates graft-versus-host disease without impacting graft-versus-leukemia effects
Authors: Byersdorfer Craig A , Beezhold Kevin J , Moore Nathan , Chiaranunt Pailin , Brown Rebecca Audrey 
Published: January 2023

Abstract
Allogeneic blood and marrow transplantation cures a variety of hematologic disorders, but its broader use remains limited by acute graft-versus-host disease (GVHD), where donor T cells attack and destroy host tissues. To explore this process mechanistically, we elucidated the role of AMP-activated protein kinase (AMPK), an intracellular energy sensor, in GHVD-causing T cells. Alloreactive T cells increased phosphorylation of AMPK as early as day 3 post-transplant (8-fold higher than naïve cells, p=0.0003), while T cells lacking AMPK caused less GVHD in two separate models. Importantly, AMPK−/− cells demonstrated equivalent cytotoxicity, with equal clearance of p815 leukemia cells, in graft-versus-leukemia experiments.
We next sought to explain our lower rates of GVHD. Surprisingly, fat oxidation, T cell autophagy, and mTOR signaling were identical between wildtype (wt) and AMPK−/− cells. However, the number of donor T cells decreased following transplantation of AMPK−/− cells (3.15 ±0.49×106vs. 1.87 ±0.53×106, p=0.0006, wt vs. AMPK−/− respectively), with fewer CD3+ cells infiltrating into GVHD target organs (e.g. liver, 206.1 ± 26.72 vs. 83.58 ± 11.10 CD3+ cells/hpf, p=0.0001). In contrast, both the percentage and total number Treg increased in recipients of AMPK−/− cells (0.85 ±0.32×104 vs. 1.69 ± 0.34×104, wt vs. AMPK−/−, p=0.004).
Thus, deletion of AMPK decreases GVHD severity but spares anti-leukemia responses. This occurs through impaired effector T cell survival, preservation of Tregs, and reduced infiltration of CD3+ cells into target organs. From these data, we conclude that targeting AMPK in donor T cells represents an attractive strategy to mitigate GVHD while still preserving graft-versus-leukemia effects.
Preloading of CD4+CD25+ Tregs to donor islets in vitro prolongs islet allograft survival
Authors: Dai Zhenhua , Zhang Shuzi 
Published: January 2023

Abstract
Despite extensive studies on regulatory T cells (Treg) in transplantation (Tx), Treg transfer alone remains ineffective in wild-type (WT) animal recipients, because only a small fraction of systemically administered Tregs can reach an allograft. The objective of this study is to optimize Treg suppression of islet allograft rejection via preloading Tregs to donor islets before Tx. We developed a unique system in which donor islets were activated and incubated with CD4+CD25+ Treg cells, resulting in intraislet recruitment of Tregs before Tx. Donor islets were stimulated by cytokines (IL-1β+ IL-6 + IFNβ) for 24 h and incubated with CD4+CD25+FoxP3+ Tregs for 48 h so that Tregs infiltrated the islets. Islets then were rested in the media for another 24 h before Tx. We found that “Treg-preloaded” islet allografts survived much longer than control islets with long-term islet allograft survival in the hepatic parenchyma in 43% of WT recipient mice (n=7) without any immunosuppressive drug. Importantly, Treg-preloaded islet allografts also survived significantly longer when transplanted in the hepatic parenchyma than in kidney capsule (MST = 62 vs. 39 days, n=7–8, P &lt; 0.05) or the portal vein (MST = 62 vs. 41 days, n=7, P &lt; 0.05). As a control, cytokine-stimulated islets with the similar culture without Treg cells were rejected at the same pace as fresh control islets (14 vs. 16 days, n=7–8, P&gt;0.05). Moreover, BrdU staining demonstrated that graft-infiltrating Thy1.1- T cells of recipients proliferated at a slower pace in islets preloaded with Tregs than in control islets (BrdU+: 21% vs. 43%) one week after Tx. In conclusion, transplanting Treg-preloaded islets in the hepatic parenchyma is a novel approach to prolonging islet allograft survival.
IL-17C ameliorates murine acute graft-versus-host disease by promoting regulatory T cell differentiation and maintaining intestinal epithelial barrier functions
Authors: Gong Huanle , Ma Shoubao , Dong Chen , Wu Depei , Liu Haiyan 
Published: January 2023

Abstract
Among IL-17 family cytokines, functions of IL-17A, IL-17F, and IL-17E (also named IL-25) are well documented in host defense against infections and inflammatory diseases. Recent studies have demonstrated that IL-17C binds to a unique heterodimeric receptor complex composed of IL-17RA and IL-17RE subunits. IL-17C was reported in the regulation of DSS-induced colitis, experimental autoimmune encephalomyelitis and other inflammatory immune disorders. However, the function of IL-17C in acute graft-versus-host-disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unknown.
In this study, IL-17C deficiency mice as donors showed a significantly accelerated aGVHD-related mortality compared with wild type donors in a fully MHC-mismatched bone marrow transplantation model (C57BL/6 to BALB/c). We found that the productions of IFN-γ by T cells were significantly increased in spleen, liver, lung as well as intestinal epithelia lymphocytes with IL-17C deficient donors. Furthermore, a reduction of FoxP3+ regulatory T cell population was observed with IL-17C−/− donors. In vitro studies showed that the percentage of Treg cells were decreased in IL-17C−/− splenocytes in a Treg polarizing condition compared with WT splenocytes. Moreover, the expression of tight junction protein occludin was decreased with IL-17C−/− donors when compared with WT controls.
In summary, IL-17C protects against aGVHD by possibly promoting Treg differentiation and maintaining intestinal barrier functions. Further studies are required to explore detailed mechanisms of its action and its potential therapeutic applications for clinical prevention and treatment of aGVHD.
Immunochemistry of the Proteins of Dog Hair
Authors: Wodehouse R. P. 
Published: January 2023

Summary and Conclusions
From dog hair there can be dissolved out with weak alkali a small amount of protein. Part of this, the “alkali metaprotein,” can be precipitated by neutralization while the rest remains dissolved but can be recovered from solution by dialysing out the salt and evaporating to dryness. This we have called “dog hair peptone.”.
These two proteins show themselves, by their skin reactions with asthmatics, to be immunologically distinct and also distinct from a peptone obtained from pure keratin, which is itself inactive, by hydrolysis, and from the serum proteins of the same species.
On the Non-Influence of Injections of Pure Proteins upon the Proportions of Globulin and Albumin in Blood Serum
Authors: Schmidt Esther Skolfield , Schmidt Carl L. A. 
Published: January 2023

Summary
Leucocyte counts and determinations of the serum proteins of rabbits receiving doses of antigenic, non-antigenic, toxic and non-toxic proteins have been made for extended periods. This was likewise done with rabbits injected with benzol to produce a leucopenia. The figures show that while the quantity of serum proteins in normal rabbits is fairly constant the protein ratio varies considerably in different animals and to a somewhat lesser extent in individual rabbits. The injection of proteins in doses used was not followed by any decided change in the protein quotient. A decrease of serum proteins follows the injection of benzol, though no change occurs in the protein quotient. A rise of globulins is not necessary for immune body production. Immunity in rabbits may be produced with well regulated dosage of antigen without giving rise to an increase of globulins. Our results are essentially in accord with recent work on the non-dependence of immunity on the serum proteins, as ordinarily determined.
The Effect of Alexin in Virus-Antivirus Mixtures
Authors: Mueller J. Howard 
Published: January 2023

Abstract
In most experiments with filterable viruses designed to show neutralizing or viricidal action by specific immune sera, the possibility of alexin exerting an effect during a preliminary incubation seems largely to have been neglected. It has been assumed that, because such mixtures may be tested only in the animal body for survival or destruction of the virus, and since alexin is there available, that it would be superfluous to add it as a separate component of the mixtures before injection. Although at first view this appears reasonable, certain observations may well cast some doubt on its validity.
It has been shown, for example, by Andrewes (1), Bedson (2) and Todd (3) that inactive mixtures of certain viruses with their specific antisera are readily dissociated by physical means (adsorption, dilution or filtration) in such a way that an active virus is again obtained. Moreover, Pentimalli (4) and Duran-Reynals and Murphy (5) have found that the virus of the Rous chicken tumor is readily adsorbed onto or into susceptible cells.
Hypersensitiveness to Diphtheria Bacterial Products
Authors: Sugg John Y. , Richardson Lurline V. , Neill James M. 
Published: January 2023

Summary
This paper reports further experiments on guinea pigs actively sensitized against diphtheria toxoid filtrate. Five points are made. First, that the anaphylactic reaction of the actively sensitized guinea pigs is inhibited by incubation of the test dose of antigen (toxin or toxoid filtrate) in mixture with antitoxic horse globulin prior to its intravenous injection. Second, that actively sensitized guinea pigs are made refractory by intravenous injection of the antitoxic horse globulin or serum shortly before the test injection of the toxin or toxoid filtrate antigen. Third, that guinea pigs anaphylactically reactive to toxoid filtrate are made refractory by subcutaneous injections of toxoid filtrate ten and seven days before the time of intravenous test, but not by similar injections of diphtheria bacterial vaccine. Fourth, that the anaphylactic reaction is inhibited if filtrate absorbed with antitoxic rabbit serum is used as the intravenous antigen, but not if filtrate similarly absorbed with antibacterial rabbit serum is used. Fifth, that the capacity of toxoid filtrate either to invoke antitoxic immunity or to actively sensitize, is greatly reduced, and under certain quantitative conditions entirely lost, if filtrate absorbed with antitoxic rabbit serum is used as immunizing or sensitizing material, while the same filtrate similarly treated with antibacterial rabbit serum retains the capacity both to invoke antitoxin production and to sensitize against the toxoid filtrate.
Neuritin Is Required for T Regulatory Cell-Mediated Suppression of the Long-Lived Plasma Cell Niche
Authors: Cooper James J. M. , Newman Stephanie , Egan Stephanie , Utley Adam , Lee Kelvin P. , Barbi Joseph J. 
Published: January 2023

Abstract
T Regulatory cells (Tregs) are critical mediators of the immune system both during active immune responses and in the maintenance of immune homeostasis. Neuritin, a highly conserved gpi-anchored protein, has been shown to regulate Treg maintenance and function in vivo. Recent data demonstrates a critical role for Tregs in the survival of bone marrow (BM) resident plasma cells (BMPCs), and that CTLA-4 expressed on Tregs limits the BMPC niche. However, the molecular mechanisms by which Tregs in the bone marrow both promote BMPC survival and limit the niche space are unknown. Here we demonstrate that Treg intrinsic neuritin levels correlate with high expression of CD44, and that activation increases the population of CD44 expressing cells in neuritin-high Tregs. This suggests that neuritin positively regulates the induction of effector Tregs. However, there is not a significant difference in the percentage of Tregs in the BM of wild type (WT) vs neuritin knock-out (KO) mice. Interestingly, in neuritin KO BM, there is a significant increase in the % of B220-ve CD138+ve BMPCs, implying that neuritin negatively regulates the BMPC pool. Previously published data from our collaborators show that CD28 is required for BMPC survival. This occurs via interaction with BM resident CD80/86 expressing dendritic cells (DCs). CTLA-4, possibly from Tregs, can also bind CD80/86 on DCs. This may sequester the survival signals to BMPCs from CD80/86. This leads to a model wherein neuritin-mediated regulation of bone marrow Treg effector functionality negatively regulates the BMPC survival niche. With the ability to target CTLA-4 with novel immunotherapeutic strategies, this understanding may allow us to enhance vaccine design and augment humoral immunity.
Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune inhibition
Authors: Rice Christopher M. , Davies Luke C. , Subleski Jeffery J. , Maio Nunziata , Andrews Caroline , Cotto Marieli Gonzalez , Lee Jung-min , Annunziata Christina M. , Rouault Tracey K. , Durum Scott K. , McVicar Daniel W. 
Published: January 2023

Abstract
Neutrophils are a vital component of the immune system, however in cancer they often play major roles in tumour progression, partly by generating reactive oxygen species (ROS) which disrupts lymphocyte function. Metabolically, neutrophils are often overlooked as purely glycolytic, however we show that immature subsets, defined by c-Kit expression, possess the capacity for oxidative mitochondrial metabolism. In limited glucose, oxidative neutrophils use mitochondrial fatty acid oxidation to fuel NADPH-oxidase (NOX) dependent ROS production. In 4T1 tumour bearing mice, mitochondrial fitness is enhanced in circulating and splenic neutrophils and is associated with the expression of c-Kit. Concordantly, tumour-elicited oxidative neutrophils are able to maintain ROS production and suppression of T-cell when glucose utilization is restricted. In accordance with these findings, peripheral blood neutrophils from cancer patient are more immature, with increased mitochondrial content and higher subsequent oxidative phosphorylation. Together our data suggest that tumours elicit oxidative neutrophil populations which are adapted to maintain immune-suppressive activity in the glucose-restricted tumour microenvironment.
The role of ERK2 in bone marrow-derived dendritic cells development and function
Authors: Jeffreys Sean Alec , Forsthuber Thomas , Negron Austin Joseph 
Published: January 2023

Abstract
Dendritic cells (DCs) regulate antigen-specific T cell responses by providing stimulatory or inhibitory signals through surface receptors and cytokines, the expression of which relies on the mitogen-activated protein kinase (MAPK) signaling pathway. In lymphocytes, the MAPK pathway is involved in differentiation, proliferation, and survival, using extracellular signal regulated kinases 1 and 2 (ERK1/2) as primary effector molecules. Importantly, ERK1 and ERK2 are not functionally redundant, despite 85% sequence homology. The role of ERK1 in DCs has been explored, however that of ERK2 remains unknown due to the lack of Erk2 Δ transgenic models. Our lab has developed a novel mouse model in which Cre-mediated deletion of Erk2 is accompanied by the expression of an eYFP reporter gene, allowing us to identify and isolate viable Erk2 Δ cells using flow cytometry. Preliminary data has shown that DCs cultured from bone marrow progenitor cells (BMDCs) exhibit altered expression of several surface receptors associated with both antigen presentation and T cell stimulation when compared to wild type BMDCs. We therefore hypothesize that ERK2 deficiency will significantly affect the ability of DCs to prime naïve T cells. We are currently investigating the functional competency of these BMDCs regarding migration, cytokine secretion, and antigen presentation. Our results will help to elucidate the role ERK2 plays in regulating DC function, potentially offering a new approach to treating T cell-driven diseases.
T-cell intrinsic RIP2 regulates pathogenic Th17 differentiation in chronic lung and vascular inflammation
Authors: Porritt Rebecca A. , Shimada Kenichi , Crother Timothy R. , Rivas Magali Noval , Chen Shuang , Arditi Moshe 
Published: January 2023

Abstract
RIP2 plays a role in sensing intracellular pathogens as an adaptor molecule for NOD1 and NOD2 intracellular receptors. While these pathways are present in many cells types, the role of RIP2 in T-cells has been much less studied. Th17 cells are a subset of CD4+ T-helper cells that produce IL17A. While Th17 cells and IL17A play an important protective role at mucosal surfaces under homeostatic conditions, and are important for immunity against certain pathogens, aberrant Th17 responses can lead to severe and chronic inflammatory diseases. Using a Chlamydia pneumoniae lung infection model, we found that Rip2 deficiency led to chronic and severe IL17A mediated inflammation. This was a T-cell intrinsic effect as naive Rip2−/− CD4+ T-cells transferred into Rag1− /− mice resulted in increased Th17 cell formation in the lungs of C. pneumoniae infected mice. This was further confirmed in an atherosclerosis model, in which naive Rip2−/− CD4+ T-cells transferred into Rag1−/− mice caused exacerbated disease, which was IL17A dependent. Intriguingly, our in vitro studies found that while RIP2 deficiency resulted in reduced Rorc expression and reduced homeostatic Th17 differentiation, loss of RIP2 also led to significantly enhanced differentiation of pathogenic Th17 cells, which was RORa dependent, but NOD1 and NOD2 independent. Conversely, overexpression of Rip2 resulted in suppression of pathogenic Th17 differentiation, which was independent of RIP2 kinase activity. Taken together, we have discovered a novel T-cell intrinsic mechanism for RIP2 in regulating the balance between pathogenic and homeostatic Th17 cells. This has broad-reaching implications for many chronic inflammatory diseases where IL17A plays a major role.
A critical role of NLRP3 inflammasome in boosting antigen-specific immunity
Authors: Qian Youcun 
Published: January 2023

Abstract
While NLPR3 inflammasome is activated by pathogen signals and danger signals like ATP and MSU, the physiological triggers of NLRP3 inflammasome activation still remain to be explored. We identified perforin as a new physiological NLRP3 inflammasome activator. We found that NLRP3 inflammasome was activated during co-cultures of antigen-specific CD8+T cells (also called cytotoxic T lymphocytes, CTL) and antigen presenting cells (APCs) in both OT-1 CTL as well as allo-antigen CTL systems. We further found that antigen presentation was required for the NLRP3 inflammasome activation in the co-culture system in vitro and in mice in vivo. The NLRP3 inflammasome activation required the direct contact of CTLs and APCs. We demonstrated that perforin in CTLs activated NLRP3 inflammasome in APCs. Through utilizing Nlrp3, Caspase-1, IL1r or perforin-deficient mice, we demonstrated that perforin-activated NLRP3 inflammasome was critical for antigen-specific CTL-mediated anti-tumor immunity and GVHD (graft-versus-host disease) pathogenesis. However, the antigen-specific CTL-mediated NLRP3 inflammasome activation was not important for host defense against intracellular bacterial pathogen and virus infections. Thus, our study reveals a positive feedback loop of adaptive immunity to promote innate immunity to amplify antigen-specific adaptive immune responses in situations of antitumor immunity and GVHD pathogenesis where innate immunity is not strongly activated.
The impact of target stiffness on NK cell activation
Authors: Friedman Daniel , Hale Alexander , White Michael , Davis Daniel M. 
Published: January 2023

Abstract
A diverse number of cell functions and behaviour are regulated by the mechanical properties of surrounding tissue. In addition, mechanical forces have been shown to impact synapse formation and signalling by T and B cells. Here, we set out to establish whether or not target cell tension impacts NK cell responses. To address this, human primary NK cells were placed on polyacrylamide substrates of varying rigidity coated with activating antibodies against NKp30 and LFA-1. NK cell activation measured by IFNγ secretion and degranulation were reduced on softer substrates. To better model the 3D interaction between NK cells and target cells, we synthesised sodium alginate cell-sized microbeads crosslinked with calcium chloride, where the inherent stiffness of the beads was controlled to be low (2-15kPa), medium (25-50kPa), or high stiffness (75-400kPa). Beads were coated with increasing concentrations of antibody to create surrogate targets with specific ligands and controlled stiffness. NK cells conjugated to stiff beads coated with mAb against NKp30, showed greater actin clustering, as well as perforin and MTOC polarisation towards the bead, to a far greater extent than those conjugated to softer beads. Thus, gel microbeads can be used to characterise the mechanosensitivity of immune synapses in 3D, and establish a role for target stiffness in NK cell activation.