bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lymphotoxin receptor beta expression by neutrophils prevents metabolic activation and colitis pathogenesis
Authors: Giles Daniel A , Riffelmacher Thomas , Zahner Sonja , Andreyev Alexander Y. , McArdle Sara , Perez Tamara , Van der Gracht Esme , Morris Venetia , Tumanov Alexei , Kronenberg Mitchell 
Published: January 2023

Abstract
Inflammatory bowel disease, while multifactorial, is largely characterized by an exacerbated intestinal immune activation. However, the critical mechanisms regulating immune activation remain to be fully defined. We have previously reported that a member of the TNF superfamily, TNFSF14 (LIGHT), and its interaction with the lymphotoxin beta receptor (LTβR), is required for preventing severe disease in a mouse model of dextran sulfate sodium (DSS) induced colitis. Thus, we aimed to determine the cell type and mechanism critical to LTβR mediated protection from DSS-induced colitis. Employing the use of LTβRfl/fl mice and tissue-specific Cre-mediated deletion, we found that neutrophils were a critical LTβR expressing cell type. Mrp8-Cre driven deletion of neutrophil LTβR expression resulted in exacerbated DSS-induced colitis and drastically increased colonic neutrophil accumulation. Mechanistically, RNASeq analysis of neutrophils revealed transcriptional alterations in genes associated with cellular metabolism, and mitochondrial function in particular. Ex vivo studies of bone marrow neutrophils from LTβRfl/fl x Mrp8-Cre mice, compared to Cre-controls, revealed increased mitochondrial mass and number, as well as elevated mitochondrial ROS production. Subsequent metabolic studies demonstrated that LTβR deficient neutrophils exhibited elevated mitochondrial respiration and glycolysis. Interestingly, these increased levels of mitochondrial mass, ROS production and glycolytic activity persist in LTβR deficient colonic neutrophils during DSS-induced colitis. In sum, our results demonstrate that neutrophil LTβR signaling plays a critical role in the immune activation associated with DSS-induced colitis.
IFN-β induces IL-6 production by B cells to promote TH17-mediated neuroinflammation
Authors: Agasing Agnieshka M , Gawde Saurabh , Siebert Nadja , Ruprecht Klemens , Paul Friedemann , Axtell Robert C. 
Published: January 2023

Abstract
Both type I interferon (IFN-I) and T helper 17 (TH17) drive pathology in neuromyelitis optica spectrum disorder (NMOSD) and TH17-induced experimental autoimmune encephalomyelitis (TH17-EAE). This is paradoxical because the prevalent theory is that IFN-I inhibits TH17 function. Here, we identify that IFN-I promotes IL-6 production from B-cells to exacerbate TH17-mediated disease in NMOSD and TH17-EAE. We identified that high levels of IL-17, IFN-I chemokines and IL-6 correlate with severe disability in NMOSD. Furthermore, IL-6 levels were significantly lower in patients treated with anti-CD20 antibody therapy. In mice, IFN-I treatment elevated IL-6 and exacerbated TH17-EAE. Strikingly, therapeutic blockade of IL-6 attenuated disease in IFN-I treated mice. We further demonstrate that IFN-I stimulates B cells to produce IL-6 which in turn drives pathogenic TH17 differentiation. These findings identify potential prognostic biomarkers for NMOSD, define molecular processes behind NMOSD pathogenesis and clarify the paradox surrounding IFN-I and TH17-induced disease.
Synergistic effect of IL-27 and retinoic acid on the expression of CD39 on mouse Treg cells
Authors: Maslanka Tomasz , Gregorczyk Izabela , Jasiecka-Mikołajczyk Agnieszka , Jaroszewski Jerzy 
Published: January 2023

Abstract
CD39, NTPDase 1, confers a stronger suppressive activity on Foxp3+CD25+CD4+ regulatory T (Treg) cells. Therefore, the induction of CD39 expression on Treg cells may be a promising drug target for autoimmune disorders. This study investigates the effect of IL-27 and all-trans-retinoic acid (ATRA) on CD39 expression by murine Treg cells in the course of in vitro activation. The mean percentage of CD39+ cells within Treg cell subset in untreated, IL-27-treated, or ATRA-treated cultures was 9.57, 13.29 and 14.31, respectively. Thus, the mean percentage of CD39-expressing Treg cells induced by exposure to IL-27 or ATRA alone (i.e. after deduction of control values) was 3.72 and 4.73. Co-exposure to IL-27 and ATRA induced a considerably greater increase in the percentage of CD39-expressing Treg cells compared to that produced by either IL-27 or ATRA alone. This effect was spectacular, since the mean percentage of CD39-expressing Treg cells was found to be 31.45. Thus, the combined exposure to IL-27 and ATRA induced CD39 expression on 21.88% Treg cells. This value was significantly greater than the mean percentage of CD39+ cells within the Treg cell subset calculated by summing up the values of this parameter obtained in the cultures treated with IL-27 or ATRA alone (i.e. 8.45%), which proves a strong superadditive effect between both agents. In conclusion, both IL-27 or ATRA have potential to induce CD39 expression on Treg cells. However, this effect seems to be relatively weakly expressed, and therefore its clinical importance is uncertain. The combined exposure to IL-27 and ATRA leads to a strong synergistic effect on CD39 expression by Treg cells, what may have important clinical implications in future.
Restoring the balance in autoimmunity: the promise of IL-2 mutein
Authors: Khoryati Liliane , Pham Minh Nguyet , Sherve McKenna , Kumari Swarnima , Bogdani Marika , Campbell Daniel J. , Gavin Marc 
Published: January 2023

Abstract
The development and function of regulatory T cells (Treg) relies on interleukin-2 (IL-2), and Treg efficiently compete with other cells for IL-2 by expressing the highest levels of the IL-2 receptor alpha-chain (CD25). Accordingly, defects in Treg and the IL-2 pathway have been reported in several autoimmune diseases including type 1 diabetes (T1D). Low-dose IL-2 therapy has shown promising results in autoimmunity; however, autoreactive immune cells can also be activated by IL-2, and the pleiotropic effects of IL-2 raise concerns regarding its widespread utility. Hence, there is a need to develop novel IL-2 based therapeutics with enhanced Treg-specificity. Hypothesizing that reduced IL-2 affinity for IL-2Rβ should increase dependency on high CD25 expression and enhance Treg-selectivity, we generated and screened twenty-eight Fc-fused murine IL-2 muteins (Fc.IL-2 mutein), and identified an optimized mutein that showed reduced signaling but prolonged association with CD25. In vivo, this optimal mutein led to greater enrichment and Ki-67 induction in Treg compared to wild-type (WT) IL-2, and reduced agonism of effector cells, resulting in an improved Treg:effector ratio. In the non-obese diabetic mouse model of T1D, we observed significant protection from disease in mice treated with Fc.IL-2 mutein compared to WT IL-2. The enhanced efficacy of the mutein was most pronounced at high doses, revealing preferential Treg stimulation across a wide dose range. Thus, Fc.IL-2 mutein treatment represents a safer and more efficient alternative for the WT IL-2 therapy, allowing for selective Treg enrichment and a targeted control of the autoimmune response.
Investigating heme regulation of REV-ERBα activity in Th17 cells
Authors: Mosure Sarah A , Kojetin Douglas , Solt Laura A 
Published: January 2023

Abstract
T helper 17 (Th17) cell dysregulation is implicated in the pathogenesis of autoimmune and chronic inflammatory diseases. Because current therapeutics exhibit negative side effects or are only successful in small patient subsets, there is a need to identify better Th17 cell-specific drug targets. We recently showed that the nuclear receptor (NR) REV-ERBα represses Th17 cell development and pathogenesis. As ligand-regulated transcription factors, NRs like REV-ERBα are amenable to pharmacological modulation, making REV-ERBα a viable target for the treatment of Th17 cell-mediated diseases. However, the mechanisms underlying ligand regulation of REV-ERBα in Th17 cells remain unclear.
REV-ERBα-mediated repression of target genes is enhanced by its endogenous ligand, heme, in other cell types, but heme’s role in Th17 cells is largely unexplored. To investigate heme’s role in Th17 cells, we differentiated naïve CD4+ T cells under Th17-polarizing conditions in vitro and found heme treatment repressed differentiation. To assess whether the effect was due to activation of REV-ERBα, we heme-treated cells lacking REV-ERBα and found the repression was partially ablated. We also found that overexpression of a REV-ERBα mutant incapable of binding heme relieved repression of Th17 cell differentiation relative to overexpression of wild type REV-ERBα. Our findings suggest that heme negatively regulates Th17 cell development, in part by activating REV-ERBα, which may require heme binding to repress target genes. Characterizing REV-ERBα regulation by heme may offer insight into mechanisms of Th17 cell pathogenesis, as well as inform the design of therapeutics for autoimmune and chronic inflammatory diseases.
Inhibition of the Cullin RING E3 ubiquitin ligase by MLN4924 targets DEPTOR degradation in Tregs to enhance their stability and functional activity
Authors: Wedel Johannes , Liu Kaifeng , Briscoe David M 
Published: January 2023

Abstract
DEPTOR is an intracellular mTOR_binding protein in CD4+ Tregs that functions to enhance lineage stability and suppressive activity. Following activation, DEPTOR is targeted for degradation by the Cullin RING E3 ubiquitin ligase, thus decreasing its expression which we postulate results in Treg instability. In this study, we wish to test if small molecule inhibitors that sustain DEPTOR levels can promote Treg function. Human CD4+ T cells were stimulated with anti-CD3/CD28 with/without MLN4924 (1–100 nM) for 6 hours. By Western blot analysis, activation was associated with a time-dependent reduction in DEPTOR protein levels, but MLN4924 sustained its expression. Using in vitro Treg stability assays, we find that human CD4+CD25hiCD127lo Tregs loose FOXP3 expression over 7 days in culture, but retain expression when cultured in the presence of MLN4924 (100 nM) (P&lt;0.01; 23% vs. 4% FOXP3+). In vivo, the treatment of C57BL/6 recipients of BALB/c cardiac allografts with MLN4924 (60 mg/kg) every 12 hours for the first five days post-transplant significantly (P&lt;0.01) prolonged allograft survival (mean survival 18 days vs. 7 days, n=6/group). Furthermore, MLN4924 was not efficient to prolong graft survival when CD4-specific DEPTOR knockout mice (C57BL/6) were used as recipients (P&lt;0.01). Collectively, these data indicate that inhibitors of the Cullin RING E3 ubiquitin ligase have potent immunosuppressive effects in part through targeting DEPTOR degradation in CD4+ T cells and by increasing Treg stability and immunoregulation in vivo. These findings have broad application following transplantation to augment tolerance, and as novel therapeutics to treat autoimmune disease.
Decreased CD4+-Th/CD8+-Tc ratio in Bone marrow at diagnosis of acute myeloid leukemia Predicts Increased Risk of Graft-Versus-Host-Disease in Transplant Patients
Authors: Wang Weiwei , Li Haibo , Fan Guang , Shen Lisong 
Published: January 2023

Abstract

Introduction
Acute myeloid leukemia (AML) is an aggressive disease with high morbidity and mortality. Transplant is one of the most important treatments for AML. However, graft-versus-host-disease (GVHD) remains one of major problems in transplant patients. Since immune repertoire plays an important role in the GVHD occurrence, we investigate the relationship between lymphocyte subsets and the risk of GVHD.

Methods
60 initial diagnostic flow data of AML transplant patients were reviewed (Oregon Health and Science University 2010 to 2016, 30 females and 30 males, with a median age of 51.417 years, range 13–72). 36 patients with GVHD including acute and chronic GVHD while 24 patients without GVHD. The lymphocyte subsets were analyzed including CD3+T-cells, CD3+CD4+Th, CD3+CD8+Tc, CD4/CD8 ratio, CD19+CD20+B, CD19+CD5+B1, CD3+CD56+NKT, CD3−CD56+NK, and three NK subsets (CD56brightNK, CD56normalNK, CD56dimNK).

Results
As to the overall survival (OS), there’s no statistic difference between age&lt;60 years old or age ≥60 years. Compared with non-GVHD group, decreased percentage (%) of Th, increased % of Tc & low Th/Tc ratio were observed in GVHD group (P=0.0281, P=0.0394, P=0.0340 accordingly). Receiver operating characteristic (ROC) analysis indicates that low Th/Tc ratio predicts increased risk of GVHD (P=0.0231, AUC=0.663, 95% Confidence Interval is 0.530 to 0.780). There’re no statistic differences between GVHD and non-GVHD for all other lymphocyte subsets percentage (P&gt;0.05).

Conclusions
AML patients with GVHD post transplant have a lower Th cell percentage and higher Tc cell percentage at diagnosis. This is to say, decreased Th/Tc ratio in BM of initial diagnosed AML patients may predict a high risk of GVHD post transplant.
T cell-mediated bone marrow and splenic hypoplasia in a mouse model of acute graft vs. host disease
Authors: Enriquez Josue , Mims Brianyell McDaniel , Furr Kathryn , Grisham Matthew 
Published: January 2023

Abstract
A major limitation with use of hematopoietic stem cell transplantation to treat relapsing hematological malignancies is the development of a potentially lethal, multi-organ inflammatory disorder called acute graft versus host disease (aGVHD). Acute GVHD-associated bone marrow (BM) suppression and lymphoid tissue (LT) hypoplasia creates protracted immunodeficiency that greatly increases the risk of infections, bleeding and death.

Objective
We wished to define the role that allogeneic CD4+ T cells play in a mouse model of aGVHD-associated BM and LT aplasia that does not require lethal myeloablative conditioning.

Methods
Allogeneic CD4+CD25−T cells (0.5×106 cells) obtained from Bl6-H2-Ab1bm12 (Bl6-BM12) donor mice were adoptively transferred into sub-lethally irradiated C57Bl6 (Bl6) recipients. Mice were monitored daily for clinical signs of aGVHD.

Results
Adoptive transfer of allogeneic but not syngeneic T cells induced a time-dependent loss of survival and remarkable reductions of cellularity in the BM and spleen. Virtually all allogeneic mice developed severe anemia at 15 days post transfer. Flow cytometric analyses revealed dramatic and significant losses of CD4+ T cells, myeloid cells and NK cells in the BM and spleen indicating BM suppression and spleen hypoplasia. Interestingly, we observed little immune cell infiltration in the lungs, liver and skin of allogeneic recipients and no evidence of disease in any tissue of syngeneic mice. These data suggest that the major target tissues in this model of aGVHD are BM and spleen.

Conclusions
When taken together, these data demonstrate that adoptive transfer of allogeneic CD4+ T cells into sub-lethally irradiated recipients induces aGVHD-associated immunodeficiency.
IL-33 signaling in the barrier tissues sustains alloimmune responses mediating graft vs. host disease
Authors: Dwyer Gaelen K , Mathews Lisa , Lucas Anna , Blazar Bruce R. , Turnquist Heth R 
Published: January 2023

Abstract

Objective
Graft vs. host disease (GVHD), where donor T cells recognize and destroy alloantigen-expressing host tissues, is a major complication after allogeneic bone marrow transplantation (alloBMT). To create space for donor stem cells and remove recipient immune cells, alloBMT protocols rely on conditioning regimens involving irradiation and/or chemotherapy. Interleukin (IL)-33 is augmented in recipient barrier tissues by conditioning before alloBMT and is a required signal to donor T cells for GVHD. In the current studies, we tested the hypothesis that the dominant role for IL-33 in GVHD lethality is to act as a sustaining signal to allogeneic T helper Type 1 (Th1) effectors in the barrier tissues.

Methods
To establish the role of IL-33 in CD4+ T cell effector function in the target tissue during GVHD, we used two CD4+-driven GVHD models. In the first, irradiated Il33−/− and Il33+/+ B6 recipients were given BALB/c alloBMT and T cells. In the second, irradiated Il33−/− and Il33+/+ bm12 recipients were given BMT and CD90.1+ B6 T cells. Donor T cell responses were characterized by flow cytometry at day 7, 14, and 28 post alloBMT.

Results
B6 Il33−/− recipients had significantly reduced frequency of IL-33 receptor-expressing CD4+Tbet+ cells in the small intestine lamina propria (SI LP), but not in the spleen (SPN) at day 7. In the MHCII-disparate B6 to bm12 GVHD model, IL-33 deficient recipients had profoundly reduced overall CD4+ donor T cells in the SI LP, but not in the SPN or lymph nodes (LN) at both day 14 and 28.

Conclusions
Our data reveal that IL-33 is not critical for donor Th1 responses in the SPN and LN, but necessary for Th1 cells to persist in barrier tissues such as the SI LP after alloBMT.
The effect of mouse cytomegalovirus infection on natural killer cell development following hematopoietic stem cell transplant
Authors: Dunai Cordelia , Aguilar Ethan G. , Khuat Lam T. , Le Catherine T. , Wang Ziming , Stoffel Kevin M. , Murphy William J 
Published: January 2023

Abstract
Hematopoietic stem cell transplant (HSCT) is a treatment for patients with hematological malignancies who are not eligible to receive intensive cytoreductive therapy. Cytomegalovirus (CMV) is an extremely prevalent infection and in immune-compromised patients, it is a significant cause of morbidity and mortality. Approximately two-thirds of seropositive patients experience CMV reactivation following HSCT. There have been reports that CMV reactivation causes increased activation of NK cells which actually benefits graft-versus-tumor effects. Our study objective is to delineate the kinetics of this effect and determine whether there are long-term functional differences in NK cells. We hypothesized that immune reconstitution is impacted by CMV infection and that the lymphopenic and inflammatory environment post-HSCT detrimentally affects the immune response to CMV infection. Using a syngeneic HSCT model in C57BL/6 mice, we studied de novo NK cell repopulation. At day 8 post-transplant, mice were inoculated with a low dose of mouse CMV. We found a significantly higher viral burden in the HSCT recipients compared to control mice. We found that CMV-specific NK cells (Ly49H+) rapidly expanded following CMV infection post-HSCT, but experienced a population collapse after two weeks. This is possibly due to exposure to a primary virus infection early on in development and/or the increased viral burden. There was a higher frequency of mature NK cells and IFN-gamma producing NK cells following CMV infection in the HSCT environment, suggestive of increased activation and accelerated differentiation. The disproportionate loss of the Ly49H+ NK cells may cause long-term functional defects in the HSCT recipient immune response.
ITK signaling differentiates GVT and GVHD after allogeneic bone marrow transplantation by regulating IRF-4, JAK/STAT and Eomesodermin expression
Authors: Karimi Mobin , August Avery , Kambayashi Taku , Huang Weishan , Jordan Martha 
Published: January 2023

Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for patients with hematologic malignancies. Donor T cells contained within the graft prevent tumor recurrence by exhibiting graft-versus-tumor (GVT) effects but also cause graft-versus-host disease (GVHD); therefore, novel treatment strategies are needed to maintain GVT while suppressing GVHD. We investigated the role of TCR-mediated ITK activation in mediating GVT vs. GVHD effects after allo-HSCT. We discovered that T cells from ITK−/−mice display a CD62Lhi CD122+ CD44hi Innate Lymphoid Cell-Like (ILCL) functional phenotype, and higher Eomes but not T bet expression compared to WT. We showed that T cells from ITK−/−mice reduced IRF-4, JAK1 and JAK2 and STAT3. T cells from ITK−/− mice displayed reduced cytokine production but showed preserved cytotoxicity after allo-HSCT. These cells also showed defective upregulation of the chemokine receptors CX3CR3, CXCR1, and CXCR6, which correlated with their reduced migration into GVHD target organs. The defective migration of ITK deficient T cells into GVHD target organs contributed to separation of GVHD and GVT effects, since ITK deficeint T cells cleared intravenously injected but not subcutaneously injected tumor cells in allo-HSCT mice. Moreover, pharmacological ITK inhibition attenuated GVHD and preserved GVT function by wild type CD8+ T cells. Together, our data suggest that ITK inhibition could be used as therapy after allo-HSCT to reduce GVHD while preserving the beneficial GVT effects by donor T cells
Vasoactive intestinal polypeptide synthesis by somatic tissues in transplant recipients limits GVHD in allo-BMT
Authors: Li Yiwen , Waller Edmund K 
Published: January 2023

Abstract
Both donor and recipient hematopoietic cells regulate GvHD in allo-BMT, but the role of somatic host tissues in the induction and maintenance of GvHD is less clear. Vasoactive Intestinal peptide (VIP) is a neuropeptide with potent immune-regulatory activity. Our goal was to examine the role of VIP synthesis by recipient tissues on donor T cell activation and GvHD in allo-BMT. We used MHC mis-matched allo-BMT models, B10.BR--&gt;B6 and Balb/c--&gt;B6, irradiating WT and VIP-KO B6 mice with 11Gy on day −1 and transplanting with 5 × 10E6 T cell depleted (TCD) bone marrow (BM) plus 0, 1 × 10E6, or 3 × 10E6 T cells from MHC mis-matched donors. B6--&gt;B6 radiation chimeras lacking VIP in either hematopoietic or non-hematopoietic cells were created by performing B6 WT--&gt;VIP-KO and VIP-KO--&gt;WT syngeneic transplants. Production of VIP in transplant recipients was visualized with immune-fluorescent staining of tissues using an anti-VIP antibody. Transplanting TCD BM plus 3 × 10E6 donor T cells from B10.BR or Balb/c donors in VIP KIO mice led significantly increased GVHD-mortality compared with WT recipients. Donor-derived T cells in VIP-KO recipients had significantly higher Th1 and Th17 polarization. B10.BR--&gt;B6 second allogeneic transplantation of radiation chimeras caused lethal GVHD mortality in VIP-KO-- &gt;VIP-KO and WT--&gt;VIP-KO mice, but not in WT--&gt;WT or VIP-KO--&gt;WT B6 mice, demonstrating the protective effect of VIP was due to synthesis by somatic recipient cells. Immunofluorescent imaging of allo-BMT recipients showed up-regulation of VIP in lungs post-transplant and high VIP production within neurons innervating the lungs. Short-term administration of VIP from D0 to D10 prevented GvHD-mortality in VIP-KO recipients transplanted BM & T cells.