bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential requirements for Th1 and Th17 responses to a systemic self antigen (167.7)
Authors: Katzman Shoshana , Gallo Eugenio , Hoyer Katrina , Abbas Abul 
Published: January 2023

Abstract
T cell-APC interactions are essential for the initiation of effector responses against foreign and self-antigens, but the role of these interactions in generating different populations of effector T cells in vivo remains unclear. Using a model of CD4+ T cell responses to a systemic self-antigen without adjuvants or infection, we demonstrate that activation of APCs augments Th17 responses much more than Th1 responses. Recognition of systemic antigen induces tolerance in self-reactive CD4+ T cells, but induction of CD40 signaling, even under tolerogenic conditions, results in a strong, antigen-specific IL-17 response without large numbers of IFN-γ-producing cells. Transfer of the same CD4+ T cells into lymphopenic recipients expressing the self-antigen results in uncontrolled production of IL-17, IFN-γ, and systemic inflammation. If the antigen-specific T cells lack CD40L, production of IL-17 but not IFN-γ is decreased and the survival time of recipient mice is significantly increased. In addition, transient blockade of the initial MHC Class II-dependent T-APC interaction results in a greater reduction of IL-17 than of IFN-γ production. These data suggest that Th17 differentiation is more sensitive to T cell interactions with APCs than is the Th1 response, and interrupting this interaction, specifically the CD40 pathway, may be key to controlling Th17-mediated autoimmunity.
Granzyme B regulates antigen-specific CD8 cell responses to Sendai virus (168.10)
Authors: Salti Suzan , Hammelev Erin , Grewal Jenny , Grossman William , Grayson Mitchell , Verbsky James 
Published: January 2023

Abstract
Introduction. Human regulatory T (T reg) cells express functional granzymes and perforin (Gzm/Prf) and can induce autologous target cell death in vitro. Prf1-/- mice die from exaggerated immune responses after viral challenges, implicating a potential role for this pathway in immune regulation. To further investigate the role of GzmB in immune regulation of viral infections, we infected wild-type (WT) mice, Gzmb-/- mice and Prf1-/- mice with Sendai virus (SeV) and characterized the magnitude of the immune response. Methods. Mice were infected with SeV and Antigen (Ag)-specific CD8 responses were measured by flow cytometry. T reg cell depletion was performed with the anti-CD25 mAb PC61. Results. Gzmb-/- mice exhibited a significant increase in the number of Ag-specific CD8 cells in the lungs and draining lymph nodes in response to SeV infection. This increase was not the result of failure in viral clearance since viral titers in Gzmb-/- mice were similar to WT mice and significantly less than Prf1-/- mice. T reg cells from WT mice expressed high levels of GzmB, and depletion of T reg cells from these mice resulted in an increase in the number of Ag-specific CD8 cells, similar to that observed in Gzmb-/- mice. Furthermore, Gzmb-/- T reg cells displayed a clear defect in their ability to suppress CD8 cell proliferation in vitro. Conclusion. Taken together, these results suggest a possible role for GzmB in the T reg cell compartment in immune regulation of viral infections.
Regulatory T cells halt islet destruction by cytotoxic T cells as an initial step in protecting against progression of autoimmune diabetes. (168.11)
Authors: Mahne Ashley , Tang Qizhi 
Published: January 2023

Abstract
In the NOD mouse model of type 1 diabetes, transfer of islet antigen-specific regulatory T cells (Tregs) isolated and expanded from BDC2.5 TCR transgenic mice halts disease progression. Having observed that BDC2.5 Tregs home to the inflammatory site of the pancreatic islets of Langerhans and that they are capable of protecting against disease development in the absence of the draining pancreatic lymph node, we sought to elucidate the mechanisms by which BDC2.5 Tregs suppress autoimmune destruction within the islets. We began with a transcriptional profiling approach to assess islet expression levels of a large panel of inflammatory mediators, chemokines, leukocyte population markers and markers of β-cell health at one week post-Treg transfer as compared to age-matched controls. We found that BDC2.5 Treg treatment induces the downregulation of a cytotoxic T lymphocyte (CTL) signature. IFNγ, Cxcl9 and granzymes A and B were among the genes most downregulated in Treg-treated islets. By flow cytometric analyses, we observed that BDC2.5 Tregs suppress IFNγ production by both CD4 and CD8 T cells within the islets. Current studies are investigating the effects of Tregs on islet CD8 T cell dynamics using multi-photon time-lapse imaging. Taken together, our results indicate that an early and critical step towards halting the progression of autoimmune diabetes by islet antigen-specific Tregs is the reigning in of β-cell destruction exerted by islet CTLs.
Characterization of the immunological synapses formed by induced T regulatory cells (168.13)
Authors: Thauland Timothy , Parker David 
Published: January 2023

Abstract
T regulatory cells (Tregs) play a vital role in the maintenance of self-tolerance and in the suppression of active immune responses. FoxP3+ Tregs arise naturally in the thymus, but can also be induced both in vivo and in vitro. The immunological synapses (IS) formed by induced Tregs (iTregs) have not been studied. We show that iTregs form either immunological kinapses or stable IS depending on the level of CD80 on the surface of APCs. As has been shown for natural Tregs, iTregs are capable of downmodulating the costimulatory ligand CD80 on the surface of dendritic cells (DCs) in an antigen-specific, CTLA-4-dependent manner. On the same timescale as CD80 downmodulation, iTregs transition from stable to motile contacts with DCs. Experiments utilizing supported planar bilayers containing pMHC, ICAM-1 and CD80 show that iTregs form motile immunological kinapses with a highly polarized cell shape in the presence of low levels of CD80. However, iTregs arrest and form stable IS when interacting with bilayers containing high levels of CD80. In experiments with blocking antibodies, we demonstrate that CD28-CD80, but not CTLA-4-CD80, interactions modulate iTreg motility. Thus, iTregs are capable of downmodulating costimulatory molecules on the surface of DCs, which in turn alters their motility.
Transient TCR engagement with an anti-TCRβ monoclonal antibody induces tolerogenic effects to allografts as well as prevents the development and reverses the onset of type 1 diabetes (169.1)
Authors: Khattar Mithun , Miyahara Yoshihiro , Schroder Paul , Mierzejewska Beata , Chen Wenhao , Stepkowski Stanislaw 
Published: January 2023

Abstract
In the current study, we investigated the immune regulatory effects of TCR engagement simultaneously by an anti-TCRβ chain mAb (H57-597) without or with antigens. We found that administration of anti-mouse TCRβ mAb resulted in a preferential reduction of antigen-reactive T cells with simultaneous enrichment (~3-fold increase) of CD4+Foxp3+ Treg cells. Moreover, administration of H57-597 mAb did not produce high levels of TNF-α, IFN-γ, IL-2 and IL-6 cytokines in serum in contrast to anti-CD3 mAb (145-2C11). Strikingly, a single injection of H57-597 mAb into RIP-OVAhi mice completely inhibited the development of type 1 diabetes (T1D) that was induced by adoptively transferred OVA-specific T cells. In NOD mice, a short course treatment with H57-597, not only prevented development of T1D (90% disease free treated at 8-weeks), but also induced remission in 7 of 7 mice treated at onset. In a transplantation model, transient H57-597 mAb treatment alone produced long-term Balb/c cardiac allograft survivals (&gt;100 days; n=9) in C57BL/6 mice. Adoptive transfer of splenocytes from the heart allograft-accepting recipients to Rag1-/- recipients (B6 background, heart grafted) showed significantly extended survival of donor-specific (Balb/c) but not third-party (C3H) heart allografts. Thus, transient modulation of TCRβ chain during an ongoing immune response exhibits potent tolerogenic effects applicable for the therapy of T cell-mediated diseases and transplant rejection.
Return of lymphocyte immunoreactivity after discontinuation of a brief course of Prograf, Cyclosporine, or Sirolimus in normal subjects. (169.13)
Authors: Lwin Wint , Park Ken , Khanna Ajai , Verma Meenakshi , Perkins David 
Published: January 2023

Abstract
The mainstay of immunosuppression is Prograf (FK), Cyclosporine (CSA), and Sirolimus (SRL). These drugs target T cells which are pivotal in transplant rejection. Little is known about their effects on length of T cell suppression once stopped. We hypothesized that T cell reactivity would return later with SRL compared to CSA or FK. 18 health volunteers were recruited. 8 received FK, 3 received CSA, and 7 received SRL. FK and CSA were taken twice daily for 3.5 days and SRL once daily for 4 days. Drugs were titrated to respective troughs (FK 8-10 mg/L, CSA 150-200 mcg/L, SRL 10-15 ng/ml). Blood were drawn at 0, 12, 24, & 48 hrs after last dose. CD4 cells were isolated using CD4 isolation beads, stimulated with CD3/28 beads, and cultured in 96 well plates. Cell proliferation and ATP concentration were measured using BrdU labeling and Cylex assay respectively. At 24 hrs, ATP concentration fold change between FK and SRL by Cylex was not statistically significant (1.0 vs. 0.8, p=0.2). T cell proliferation measured by BrdU compared to time 0 was significant in 2/8 patients at 12 & 24 hrs and 4/8 patients at 48 hrs in FK group, 1/3 patients at 12 & 48 hrs in CSA group, and 6/7 patients at 12 & 48 hrs in the SRL group (p&lt;0.05). Proportions were not significant but did trend towards significance in SRL compared to FK at 12 hrs (p=0.07). In conclusion, SRL was not associated with longer immunosuppression of T cells stimulated in-vitro compared to patients taking FK and CSA.
Allograft survival is prolonged in the absence of NKG2D (169.19)
Authors: Wai Lu-En , Wang Mouer , Piard-Ruster Karine , Martinez Olivia , Krams Sheri 
Published: January 2023

Abstract
NKG2D is expressed by Natural Killer (NK cells) and subsets of T cells. On NK cells, NKG2D functions as a stimulatory receptor that induces effector functions. We have demonstrated increased expression of NKG2D ligands on rejecting grafts and enhanced infiltration of NKG2D-expressing cells in allografts during rejection. To further examine the role of NKG2D in graft survival we utilized Klrk1 mice that are deficient for NKG2D as recipients of cardiac or small intestine allografts. Groups (n=4-6) of C57BL/6 (H-2b) or NKG2D deficient Klrk1 mice (H-2b) received heterotopic donor hearts or vascularized, orthotopic small intestine grafts from BALB/c (H-2d) or BALB/c x C57BL/6 F1 mice (H-2d/b). Some groups of mice also received 200μg (heart) or 500μg (intestine) anti-CD40L mAb (MR1) at transplant. Cardiac allograft survival was similar in wild-type and Klrk1 mice although intestinal allograft survival was prolonged in Klrk1 mice. Treatment with MR1 prolonged cardiac allograft survival that was further enhanced in the absence of NKG2D. Treatment with MR1 did not prolong survival of intestine allografts in wild-type recipients. Quite dramatically, however, treatment with MR1, significantly (p=0.007) prolonged intestinal allograft survival in Klrk1 mice. Prolongation of intestinal graft survival in the absence of NKG2D and CD40-CD40L interactions suggest that the addition of therapeutics to block NKG2D has great potential for improving costimulation blockade based therapies
Janus kinase 2 offers a precise therapeutic target against DC stimulated alloreactivity in transplantation (169.21)
Authors: Betts Brian , Abdel-Wahab Omar , Hanash Alan , St. Angelo Erin , van den Brink Marcel , Levine Ross , Young James 
Published: January 2023

Abstract
JAK2 is critical to cytokine signaling and has a specific role in mediating alloreactivity. We have demonstrated that specific JAK2 inhibition with TG101348 suppresses alloimmunity stimulated by human dendritic cells in vitro, while maintaining immunity against viral antigens. JAK2 inhibition also extends survival in a mouse graft-versus-host disease (GvHD) model. Methods: Major MHC-mismatch models were used in human and mouse experiments. Human moDC and moDC:T cell cultures were treated with either TG101348 (1uM) or vehicle. Mice underwent 850 cGy irradiation followed by T cell-depleted marrow and splenic T cells. TG101348 (60mg/kg) or vehicle was administered per oral gavage daily. Results: JAK2 inhibition reduced the expression of CD83 and CCR7 in 2-day cytokine-matured moDCs (p&lt;0.05) and suppressed T cell proliferation in a 5-day alloMLR (p&lt;0.005). JAK2 blockade preserved allogeneic Tregs (p=NS), and enhanced the Treg:CD8+CD25+ T cell ratio (p&lt;0.05). T cells exposed to JAK2-inhibited DCs maintained tolerance to alloantigen restimulation, with preserved response to flu-loaded autologous moDCs. JAK2 inhibition delayed the onset of GvHD and improved survival in BALB/c mice that received B6 marrow and T cells (median survival JAK2 inhibitor 35 days vs vehicle 25 days, p&lt;0.005). All mice engrafted. Conclusions: JAK2 offers a novel, specific therapeutic target against GvHD and allograft rejection by suppressing DC allostimulation of T cells, without broader immune impairment.
Expression of microRNA miR-182 is induced in alloimmune responses (169.23)
Authors: Wei Liang , Pham Betty , Wang Mouer , Harris Aleishia , Phillips Lori , Piard-Ruster Karine , Martinez Olivia , Krams Sheri 
Published: January 2023

Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by translational repression or mRNA degradation. We defined a profile of miRNAs expression during graft rejection and suggested that the miRNA miR-182, which is a member of the mir-183-miR-96-miR-182 cluster, is significantly increased in the allograft, graft infiltrating cells, spleen and peripheral blood lymphocytes during rejection. To further define the function of miR-182 in alloimmune responses, splenocytes isolated from C57BL/6 or BALB/c mice were used as responders or stimulators in a one-way MLR. Proliferation was measured by [3H]-thymidine uptake on days 0 to 7 and cells were collected at each time point and RNA isolated to detect kinetic expression of miR-182 and its potential targets. Expression of miR-182 increased specifically in allo MLR between days 2-3 and reached peak expression on day 5. Computational target prediction suggested the genes Foxo1, Rac1, Bcl2 and Grb2 as putative targets of miR-182. The four genes all decreased from days 4 to 6 specifically in the allo MLR group supporting that increased expression of miR-182 may inhibit expression of these genes. CONCLUSION. Our results suggest an important role of miR-182 in alloimmune responses. Further studies may result in novel therapeutics to control the proliferation of alloreactive cells.
NK cells mediate chronic kidney allograft injury (169.26)
Authors: Zhang Zhu-Xu , Jiang Jifu , Huang Xuyan , Yin Ziqin , Liu Weihua , Garcia Bertha , Jevnikar Anthony 
Published: January 2023

Abstract
Chronic allograft injury remains the leading cause of kidney graft loss after transplantation and no-specific therapy currently exist. We have recently demonstrated that NK cells can kill syngeneic tubular epithelial cells (TEC) and participate in kidney ischemia-reperfusion injury. In this study, we investigated the capacity of NK cells to mediate kidney injury in transplantion. C57BL/6 (B6, H-2b) kidneys were transplanted into nephrectomized F1 (B6 x BALB/c, CB6F1) mice. Serum creatinine levels increased from baseline (22+5 uM, n=8) to 38±6 uM (n=6, P&lt;0.001) at 60 days post transplant, demonstrating a clear loss of kidney function. Infiltrates and low grade renal tubular cell injury were consistently present in B6-to-CB6F1transplants suggesting a non T cell pathway. This was supported by results using a B6-Rag-/--to- CB6F1Rag-/- (B6Rag-/-xBALB/cRag-/-) F1 kidney transplant that eliminates T and B cell but not NK cell participation. Similar levels of kidney dysfunction (creatinine: 34+8 uM, n=6, p&lt;0.01) and histological injury were observed 65 days post transplant. Finally depletion of NK cells prevented kidney injury (25±6 vs 34+8 uM in no antibody injection, n=6, p&lt;0.05) as well as improved histology. In conclusion, these data demonstrate for the first time a critical role for NK cells in mediating chronic kidney injury, which is independent of T and B cells. NK cells are newly appreciated and formidable effectors to chronic kidney injury and graft loss.
Regulatory T cells establish and maintain chimerism after in utero hematopoietic cell transplantation (169.30)
Authors: Nijagal Amar , Le Tom , Wegorzewska Marta , Tucker Andrew , Tang Qizhi , MacKenzie Tippi 
Published: January 2023

Abstract
Background: In utero hematopoietic cell transplantation (IUHCTx) is a promising strategy to treat congenital diseases and induce donor-specific tolerance. The role of regulatory T cells (Tregs) in the establishment and maintenance of chimerism after IUHCTx has not been established. We characterized the expansion of Tregs in a wildtype (wt) and antigen-specific setting after IUHCTx. Methods: We analyzed chimerism in BALB/c fetuses 5 weeks after allogeneic IUHCTx and characterized their T cell and APC subsets. To quantify antigen-specific Tregs, BALB/c cells were transplanted into T cell receptor transgenic fetuses that recognize BALB/c antigen via the direct (4C) or indirect (TCR75) pathway. Results: In wt animals, we found an equivalent percentage of Tregs among uninjected animals, chimeras, and injected non-chimeras. The percentage of activated CD44+ Tregs was significantly higher among chimeras compared to uninjected controls. APC maturation markers (B7 and CD40) were elevated in donor and host-derived pDC and B cells of chimeric animals. In both 4C and TCR75 recipients, chimeric mice showed deletion of T effector cells and expansion of Tregs in the thymus and spleen. 4C animals losing chimerism showed a decrease in the number of Tregs. Conclusions: Our data suggests that Tregs interact with both host and donor-derived APC and undergo activation. Successful Treg induction is important for establishing and maintaining chimerism after IUHCTx.
Critical role of STAT3 in IL-17-mediated survival of fibroblast-like synoviocytes in rheumatoid arthritis. (171.16)
Authors: Cho Mila , Lee Seon-Yeong , Son Hye-Jin , Ryu Jun-Geol , Kim Eun-Kyung , Kim Ho-Youn 
Published: January 2023

Abstract
Fibroblast-like synoviocytes (FLS) are major cell population of the pannus that invades adjacent cartilage and bone in rheumatoid arthritis (RA). The study was undertaken to determine the effect of interleukin-17 (IL-17) on the survival and/or proliferation of FLS from RA patients and to investigate whether signal tranducer and activator of transcription 3 (STAT3) is implicated in this process. The expressions of Bcl-2 and Bax in FLS were determined using real-time PCR and western blot analysis. The expression of CD55, Bcl-2, Bax, IL-17 and phosphoSTAT3 in synovial tissues were investigated by immunohistochemistry. Apoptosis of FLS was detected by Annexin V/propidium iodide staining and/or phase contrast microscopy. The proliferation of FLS was determined by CCK-8 ELISA assay. The pro-apoptotic Bax is decreased and anti-apoptotic Bcl-2 is increased in FLS from RA patients compared with in that from OA (Osteoarthritis) patients. IL-17 upregulates the expression of Bcl-2 in FLS from RA patients, not in FLS from OA patients. STAT3 was found to mediate IL-17-induced Bcl-2 upregulation in FLS from RA patients. In addition, IL-17 promotes the survival and proliferation of FLS from RA patients. Most importantly, treatment with STAT3 inhibitor reverses the protective effect of IL-17 on FLS apoptosis induced by SNP.
Macrophage scavenger receptor 1 (Msr1) promotes autoantibody-mediated arthritis by impairing B cell tolerance (171.18)
Authors: Haasken Stefanie , Mueller Daniel , Binstadt Bryce 
Published: January 2023

Abstract
Peripheral tolerance is achieved through several mechanisms, including induction of the hyporesponsive state of anergy in potentially autoreactive lymphocytes. The class A macrophage scavenger receptor, Msr1, is reported to participate in the maintenance of immunological tolerance by performing functions such as the clearance of apoptotic debris and the tonic sampling of self-antigens. We evaluated the role of Msr1 in a mouse model of autoantibody-dependent arthritis. Genetic deficiency of Msr1 in the K/BxN TCR transgenic model (Msr1-/- K/BxN) decreased the incidence and severity of arthritis. However, arthritis induced by transfer of arthritogenic autoantibodies was unimpaired in naïve mice lacking Msr1, suggesting that Msr1 deficiency in K/BxN mice affected the pathogenic events preceding autoantibody synthesis. Indeed, antibodies against the key autoantigen in this model, glucose 6-phosphate isomerase (GPI), were undetectable in Msr1-/- K/BxN mice, despite the presence of an expanded population of GPI-specific B cells. We did not observe any defect in T cell numbers or function. We hypothesized that Msr1 might control the availability of autoantigen and found that Msr1-/- macrophages displayed impaired uptake of GPI. Taken together, these data suggest a model in which deficiency of Msr1 can lead to a higher concentration of soluble autoantigens, resulting in B cell anergy and protection from autoimmune disease.
Complement Orchestrates T cell response during Mesenteric Ischemia Reperfusion Injury in Autoimmune Prone Mice. (171.22)
Authors: Ioannou Antonis , Lapchak Peter , Kannan Lakshmi , Rani Poonam , Dalle Lucca Jurandir , Lambris John , George Tsokos 
Published: January 2023

Abstract
Ischemia reperfusion injury is a type of injury seen in clinical conditions, such as trauma, hemorrhagic shock, organ transplantation, revascularization processes, and autoimmune diseases like systemic lupus erythematosus. MRL/lpr mice due to their autoimmune background present with accelerated mesenteric ischemia reperfusion injury (IR/I). To evaluate the effect of complement inhibition on tissue damage after mesenteric IR in MRL/lpr mice, we depleted complement using Cobra Venom factor (CVF) or blocked C5a receptor with a C5aR antagonist, and performed intestinal ischemia reperfusion. First, we confirmed that CVF treatment completely depleted C3 from the mice serum. Next, we found that the treatment with either CVF or C5aR antagonist attenuated intestinal injury following intestinal IR. Notably, depletion of complement increased the presence of IL-10 producing CD4+ cells (Tr1) and IL-10 producing Th17 cells in the intestine. These results suggest that complement may regulate the T-cell response during intestinal ischemia reperfusion injury.