bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating the source of viral-specific memory T cells in glioblastoma
Authors: Kleist Sierra A , Musial Shawn C , Isaacs Jordan F , Degefu Hanna N , Skorput Alexander G , Rosato Pamela C 
Published: August 2023

Abstract
Glioblastoma (GBM) is an aggressive primary brain tumor that is invariably fatal. Immunotherapies have largely failed and a better understanding of the unique brain tumor immune environment is needed. Being historically thought of as immune-privileged, immune cell populations within the brain and brain tumors have been understudied. One such population is resident memory T cells (TRM). In healthy and malignant peripheral tissues, TRM can provide long-term protection against reinfections or cancers, however the role of TRM in the context of the brain and brain tumors is not fully understood. Our lab has discovered that memory T cells specific for common viral infections populate human brain tumors to high frequencies and express markers indicative of tissue residency. We also find these virus-specific memory T cells (vsTM) in mouse models of GBM, despite the absence of infection. Surveillance of tumors by bystander (non-tumor specific) memory T cells is understudied despite their potential to contribute to anti-tumor immunity. Indeed, the source of these cells is unknown; they may originate from circulating memory T cells that infiltrate the tumor, and/or pre-existing TRM that were in the brain prior to tumor formation. To dissect the origin of vsTM in brain tumors we established mouse models with distinct memory T cell compartments. Preliminary data suggests that pre-established vsTRM in healthy brain are the main contributors to tumor vsTM. Future work will assess if vsTM are resident within tumors, and extend studies to virus-specific T cell populations in human brain tumors. Our findings will broaden our understanding of GBM immunosurveillance, and provide valuable insights for the development of novel T cell-based immunotherapies.
Supported by grants from the Dartmouth Cancer Center
CD8+ T Cells Differentiate into a Potent CD43+ Effector Population During Acute Allograft Rejection
Authors: Krummey Scott , Cohen Gregory , Kallarakal Melissa 
Published: August 2023

Abstract
Although acute rejection threatens allograft function, little is known about the functional properties of graft-specific effector CD8+ T cells. Using the Balb/c H-2L(d) into C57Bl/6 H-2(b) fully allogeneic skin graft model, we identified host CD8+ T cells specific for the L(d) QL9 epitope using MHC tetramers. L(d) QL9+ T cells increased in number and differentiated into CD44+ effector populations by day 10 post-graft with Balb/c skin, but not third-party C3H skin. Using dimensionality reduction analysis, we found that a population of CD62Llo effector CD8+ T cells expressing the surface receptor CD43 formed during graft rejection in the draining lymph nodes, spleen, and blood. The frequency of CD43+ effectors peaked from day 10–14 post-graft, indicative of a short-lived population. CD43+ CD8+ T cells displayed potent effector functions relative to CD43− cells, including Granzyme B expression, IFN-γ/TNF-α co-production, and accelerated Balb/c graft rejection (p&lt;0.01 for each). Adoptive transfer experiments revealed that only 31% of the L(d) QL9+ T cells divided on day 14 post-graft, versus 95.6% of OT-I T cells after mOVA skin grafting. CD43 expression was only expressed on cells in their final division. Finally, we rechallenged flow cytometry purified CD45.1 CD43+ and CD43− effector CD8+ T cells with a Balb/c skin graft, and found that approximately half of the CD43− population became CD43+, while all of the CD43+ population remained CD43+ on day 21 (49% vs 96%, p&lt;0.001). Together, these data demonstrate that CD8+ T cells differentiate into a CD43+ population after grafting that undergoes weak proliferation and yet is functionally potent.
Mechanisms of aberrant tissue residency programming of uterine natural killer cells in uterus transplantation
Authors: Porrett Paige , Greene Morgan E , Asiimwe Rebecca , Bell Markayla , Wright Emma , Gunn Deidre , Richter Holly 
Published: August 2023

Abstract
Uterine natural killer cells (uNK) are the most common human decidual lymphocytes, but the origin and ontogeny of uNKs remain unclear. Studies of human uterus transplant recipients (UTx) suggest that uNKs originate in the blood, but how these cells become tissue resident and differentiate into decidual NK cells is unknown. We studied the molecular mechanisms governing uNK tissue residency in human endometrium using single-cell RNA-seq and flow cytometry analyses. trNK cells with a CD49a+ CD16− phenotype were the most abundant CD56+ cells in the endometrium of 5 healthy control volunteers (HCs) [27±17% trNK vs. 4±2.7% CD49a− CD16+ conventional NK cells (cNK); p&lt;0.02]. trNK cells differentially expressed genes associated with T cell tissue residency, such as ITGAE and ZNF683, compared to cNK. Although peripheral blood NK cells can express CD103 when incubated with TGF-β, trNKs upregulated CD103 expression in response to IL-15 alone in vitro. Given the dependency of CD103 expression on NFAT signals, we studied CD103 expression on trNKs by incubating human endometrium (n=7) with the calcineurin inhibitor FK506, which decreased IL-15-induced upregulation of CD103 (81% CD103+ [IL-15 alone] vs. 70% CD103− [IL-15 + FK506]; p=0.02). We next tested the in vivo relevance of these findings by comparing the frequency of trNKs in endometrial biopsies of five HCs with two biopsies of one UTx on FK506 immunosuppression. The UTx recipient had significantly fewer trNKs among CD45+ cells in two biopsies (HC: 27±17% vs. UTx: 4.3±2%; p=0.04). Altogether these findings suggest that IL-15-induced calcium signals influence uNK tissue residency, with significant implications for transplant recipients.
This work was supported from UAB AMC21 and support of the uterus transplant program from the University of Alabama at Birmingham. P. Porrett is additionally supported by NIH R01 AI145905.
Water channel Aquaporin 4 is required for T cell activation
Authors: Nicosia Michael , Beavers Ashley , Kish Danielle , Farr George W , McGuirk Paul R , Pelletier Marc F , Fairchild Robert L , Valujskikh Anna 
Published: August 2023

Abstract
Aquaporins are a family of ubiquitously expressed transmembrane water channels. We have previously reported that Aquaporin 4 (AQP4) is expressed on T cells and that treatment with a small molecule AQP4 inhibitor significantly delays T cell mediated heart allograft rejection. The goal of this study was to identify mechanisms of prolonged graft survival following AQP4 blockade.
Stimulation of murine WT T cells + AER-270 or AQP4−/− T cells resulted in decreased expression of T cell activation markers CD25 and CD44, and reduced cell volume when compared to control WT T cells. In addition, the absence or inhibition of AQP4 also limited IL-2 production by T cells following stimulation. Intact AQP4 was also required for optimal IFNg production by T cells. Analogously, AQP4 inhibition significantly limited the ability of human T cells to proliferate following TCR stimulation. We then examined the role of AQP4 in TCR signal transduction and found that AQP4 was required for nuclear translocation of NF-KB and NFAT and for optimal calcium flux following TCR stimulation. Either the absence or inhibition of AQP4 impaired TCR signal transduction as early as phosphorylation of Lck (pY394), ZAP70 (pY319) and LAT (p171). AQP4 was previously shown to associate with the actin cytoskeleton in other cell types, we next tested its involvement in TCR polarization/capping. We found that loss of AQP4 resulted in significantly impaired TCR capping and dysfunctional post-TCR stimulation actin remodeling kinetics.
Our findings reveal novel mechanisms underlying the importance of AQP4 in optimal T lymphocyte activation and identify AQP4 as a potential therapeutic target for preventing TCR-mediated T cell activation in solid organ transplantation and other diseases.
Solid organ and vascularized composite allotransplantation have distinct requirements for localized delivery of enhanced costimulation blockade to control rejection
Authors: Raimondi Giorgio , Bodine Amy , Nambiar Monessha , Calderon-Colon Xiomara , Tiburzi Olivia , Hou Shenda , Morrissey Molly , Foley Brendan , Zhang Yichuan , Patrone Julia , Schneider Joel 
Published: August 2023

Abstract
We recently demonstrated, in a mouse heart transplant model, the therapeutic effect of Enhanced Costimulation Blockade: the transient combination of CTLA4-Ig with the JAK inhibitor Tofacitinib (Tofa). In the same model, we also proved the efficacy of a graft-localized delivery by means of a Tofa releasing hydrogel (Tofa-Hydro). In this study, we implemented a mouse orthotopic hind-limb VCA model to delineate any differential drug delivery requirement. Moreover, we explored the potential of Tofa-containing lipid nanoparticles (LNp) in achieving selective targeting of immune cells and its therapeutic effect. Local injections of Tofa-Hydro combined with CTLA4-Ig promoted VCA survival, although with a smaller therapeutic benefit (MST=23 days vs CTLA4-Ig-only MST=14 days). We identified a LNp formulation with negligible toxicity and favorable Tofa encapsulation efficiency. Live animal imaging and flow analysis indicated these particles have the unique property of accumulating in draining lymphoid tissues, with minimal distribution to other tissues, and deliver their cargo to multiple immune cells. Four post-transplant SQ injections of Tofa-LNp (with CTLA4-Ig) promoted graft survival longer than Tofa-Hydro (MST&gt;60 days). Our results reveal that SOT and VCA differ in the topography of inflammatory events that contribute to rejection. This novel observation suggests that different activatory mechanisms contribute to allopriming in the two systems, although they share utilization of JAK signaling pathways. Nevertheless, our study demonstrates the efficacy of localized actuation of enhanced costimulation blockade in achieving safer regulation of rejection.
DOD Award # W81XWH-18-1-0789
Type-1 regulatory T cells are critical for curative immunotherapy outcomes
Authors: Zhang Ping , Gartlan Kate H , Minnie Simone A , Yeh Albert , Takahashi Shuichiro , Atilla Erden , Nemychenkov Nicole S , Boiko Julie R , Schmidt Christine R , Legg Samuel R W , Sekiguchi Tomoko , Ensbey Kathleen S , Koyama Motoko , Furlan Scott N , Hill Geoffrey R 
Published: August 2023

Abstract
IL-10 producing CD4+ type-1 regulatory T cells (Tr1) mediate immune tolerance during chronic infection, autoimmunity, and transplantation. We previously demonstrated that eomesodermin (Eomes) promotes Tr1 cell (Eomes+IL-10+) development after allogenic bone marrow transplantation (alloBMT). Here we define the differentiation trajectory of Tr1 cells and the functional states therein. Eomes−IL-10−, Eomes+IL-10− and Eomes+IL-10+ subsets (defined by mCherry and GFP expression respectively) were FACS sorted after alloBMT and transferred into secondary recipients. Eomes+IL-10+ T cells were stable in phenotype after transfer while the Eomes+IL-10− T cell subset differentiated into Eomes+IL-10+ Tr1 cells. Tr1 differentiation was associated with progressive enrichment for cytotoxicity (Perforin, Nkg7, Granzyme K, Tnfrsf9), immune regulatory (IR) (Tim-3, Lag3, Tox, Nr4a2) and chemokine (Ccl3, Ccl4, Ccl5) RNA expression. Equivalent IR, cytotoxic and cytokine/chemokine expression was confirmed at a protein level. The conditional deletion of Eomes in CD4 T cells prevented Tr1 differentiation and resulted in impaired cytotoxicity in vivo, the accumulation of donor CD11c+ dendritic cells, mixed donor chimerism and leukemia relapse, consistent with a critical role for this lineage in tolerance, engraftment and graft-versus-leukemia effects. The deletion of Eomes from CD19-targeted chimeric antigen receptor (CAR) T cells, reduced cytotoxic molecule expression (perforin, granzyme A/B) in CD4 CAR T cells and resulted in immune escape due to CD19 antigen loss in leukemia cells. In sum, Tr1 cells mediate critical Eomes-dependent cytotoxic and regulatory function that are critical for curative immunotherapy outcomes.
TIGIT agonism alleviates costimulation blockade-resistant CD8 memory T cell responses in transplant
Authors: Hartigan Christina R , Wagener Maylene , Ford Mandy L 
Published: August 2023

Abstract
Tcell Immunoreceptor with Igand ITIM domains (TIGIT) is an inhibitory molecule that has been well characterized in cancer and autoimmunity. We recently published that TIGIT agonism prolongs graft survival in a mouse model of transplantation and showed that this was in part dependent on TIGIT-expressing Tregs. However, we have also observed that TIGIT expression is upregulated on memory T cell subsets that mediate costimulation blockade-resistant rejection in transplantation. In the present study, we aimed to determine the cell intrinsic role of TIGIT agonism on memory CD8 T cells in a murine model of transplant. To do this, we induced immunological memory by performing an adoptive transfer of OT-I T cells prior to infecting animals with Listeria monocytogenes that expresses the model antigen OVA. 30-days after infection, we performed OVA-expressing skin grafts and treated with the costimulation blockade therapeutic CTLA-4Ig or CTLA-4Ig + TIGIT agonist. TIGIT agonist + CTLA-4Ig prolonged graft survival (MST= 14d) compared to CTLA-4Ig treatment alone (MST= 11d, p=0.077) and reduced antigen-specific CD8 T cell infiltration into the graft (4-fold reduction, p=0.017). TIGIT agonist also led to the sequestration of CXCR3 expressing OT-I cells in the draining lymph nodes and impaired trafficking of CXCR3+ OT-I cells to the graft compared to CTLA-4Ig alone. Additionally, TIGIT agonism in vivo led to a decrease in the frequency of TIGIT+IFNg+OT-I cells during ex vivo restimulation (2-fold decrease in CTLA-4Ig + TIGIT agonist vs. CTLA-4Ig alone, p=0.028). TIGIT agonism suppresses memory CD8 T cells in transplant by inhibiting their trafficking and decreasing cytokine production to alleviate costimulation blockade-resistant rejection.
Supported by grants from NIH (5R01AI073707-10, 1F31AI161911 - 01A1)
The adaptation model of immunity: allograft rejection versus allograft adaptation
Authors: Manjili Masoud H 
Published: August 2023

Abstract
Rejection of allografts and acceptance of grafts between identical twins appear to be associated with allogeneity or nonself entity of allografts as suggested by the self-nonself (SNS) model of immunity. Nevertheless, such guilt by association does not necessarily follow a cause-effect direction. The adaptation model proposes that graft rejection or tolerance is determined by the expression of the tissue-specific adaptation receptors (AdRs) which are linked to anti-apoptotic pathways for tolerating the recipient’s alloreactive immune response induced by surgical procedure during organ transplantation. A better engraftment of less matched living-donor organs compared with matched cadaver-donor organs is because of a severely altered AdRs in the latter. To this end, tissue adaptation to an anti-graft immune response suggests that AdRs can be restored in allografts if treated properly. Re-transplantation studies demonstrated that second fresh skin allograft rejection while the first adapted allograft from the same donor remaining viable in the presence of all-reactive T cells. Also, constitutive expression of a bidirectional AdR, B7-H1 linked to Bcl-xL anti-apoptotic pathway, in the cornea and retina protects them from rejection while block-ade of B7-H1 accelerates allograft rejection. Also, severe GVHD following autologous stem cell transplantation could be due to chemotherapy-induced alterations in the AdRs in target tissues. This is supported by demonstrating that autologous TRM cells that are involved in local tissue homeostasis but not alloreactive TEM cells are involved in GVHD. Interestingly, restoration of the putative AdR, B7-H1, expression by parenchymal tissues could prevent or ameliorate GVHD in humans.
This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH2210793. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Department of Defense. This work was also supported by multi-investigator pilot funding from the VCU Massey Cancer Centre, supported in part with funding from NIH/NCI Cancer Centre support grants P30 CA016059.
Tapinarof ameliorates rejection in a human skin grafted model of face transplantation
Authors: Crisler William J , Win Thet Su , Gehad Ahmed , Barrera Victor , Ho-Sui Shannan , Clark Rachael A 
Published: August 2023

Abstract
T cell mediated immune rejection is the primary barrier to broader implementation of face transplants (vascularized composite allografts, VCA). Our bulk and single cell transcriptional profiling of human face transplant rejection demonstrated that VCA rejection is an INFγ driven cytotoxic process with unique induction of skin specific immunoregulatory pathways including SOCS1, KIR3DL2, and LY9. Tapinarof is a novel small-molecule topical aryl hydrocarbon receptor agonist and antioxidant that is effective in treating psoriasis and atopic dermatitis. Patients who cleared on once a day topical tapinarof remained clear for an average of four months after discontinuation, suggesting it has durable immunoregulatory effects in skin. We modeled VCA by grafting NSG mice with freshly excised, living, immunologically intact adult human skin. Once healed, 5×106 allogeneic PBMCs from a second unrelated human donor were infused via tail vein. The inflamed skin mimicked VCA rejection after 21 days, with grafts showing epidermal injury, T cell infiltration, dyskeratosis, and genetic signatures of cytotoxicity, antigen presentation, and INFγ signaling. Topical tapinarof ameliorated this inflammation, with fewer T cells and reduced antigen-specific T cell activation. Induction of immunoregulatory pathways was also noted, including upregulation of SOCS1 signaling, TREX1 mediated reductions in cytosolic nucleotide sensing, and IL1RN inhibition of IL-1 mediated inflammation. Tapinarof could be a novel therapy for VCA rejection that does not require systemic immune suppression. Our results suggest that strengthening immunoregulatory networks in skin is a viable approach to combat inflammation and promote tolerance in VCA rejection.
NIH T32 Training Grant 2T32AR007098-47 Dept. of Dermatology, Harvard Medical School RT170025 (P.I. Rachael A. Clark) Department of Defense - congressionally Directed Medical Research Programs; "T cells and Rejection in Vascularized Composite Allografts).
Mapping the T cell repertoire to a complex defined gut bacterial community
Authors: Nagashima Kazuki , Fischbach Michael A 
Published: August 2023

Abstract
Certain bacterial strains from the microbiome induce a potent, antigen-specific T cell response. Previous reports have profiled strains from the gut microbiome under artificial conditions of mono-colonization. While this approach can identify strains that have a potential to modulate immune cell function, it does not reveal how a strain behaves in the physiological context of a complex community. Here, we colonize germ-free mice with a complex defined community (&gt;100 bacterial strains) and profile T cell responses to each strain individually. Unexpectedly, the pattern of T cell responses suggests that many T cells in the gut repertoire recognize multiple bacterial strains from the community. We constructed T cell hybridomas from 92 T cell receptor (TCR) clonotypes; by screening every strain in the community against each hybridoma, we find that nearly all of the bacteria-specific TCRs exhibit a one-to-many TCR-to-strain relationship, including 13 abundant TCR clonotypes that are polyspecific for 18 Firmicutes in the community. By screening three pooled bacterial genomic libraries against 13 pooled hybridomas, we discover that they share a single target: a conserved substrate-binding protein (SBP) from an ABC transport system. Treg and Th17 cells specific for an epitope from this protein are abundant in community-colonized and specific-pathogen-free mice. Our work reveals that T cell recognition of Firmicutes is focused on a widely conserved cell-surface antigen, opening the door to new therapeutic strategies in which colonist-specific immune responses are rationally altered or redirected.
This work was supported by the Stanford Microbiome Therapies Initiative, the Human Frontier Science Program LT000493/2018-L (K.N.), a Fellowship from the Astellas Foundation for Research on Metabolic Disorders (K.N.), a research grant from Kanae Fundation for the Promotion of Medical Science (K.N.), an HHMI-Simons Faculty Scholar Award (M.A.F.); the Leona M. and Harry B. Helmsley Charitable Trust (M.A.F.); NIH grant DK110174 (M.A.F.); the Chan Zuckerberg Biohub (M.A.F.); Stand Up to Cancer (M.A.F.); and the MAC3 Impact Philanthropies (M.A.F.).
Zinc Treated Engineered Human Dendritic Cells Capable of Synthesizing High Active Vitamin D and Retinoic Acid Concentrations Enhance Gut-homing Regulatory T Cell Induction
Authors: Ali F N U Shaikh Nisar , Abdalla Maisa I , Cannon Lisa M , Zhang Xiao-Bing , Baylink David J , Tang Xiaolei 
Published: August 2023

Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the gastrointestinal tract (the Gut). Available IBD therapies can cause severe side effects, and many patients either fail to respond to the treatment or lose therapeutic effects with time. Hence, IBD therapy is still an unmet medical need. We recently proposed to enhance the induction of regulatory T cells (Tregs) expressing gut-homing molecules (gut-homing Tregs) to control chronic gut inflammation in IBD patients without compromising systemic immunity. We have shown that dendritic cells (DCs), engineered to de novo synthesize high concentrations of the active vitamin D (1,25-dihydroxy vitamin D or 1,25[OH]2D) and retinoic acid, increase the induction of gut-homing Tregs phenotypically and functionally in healthy mice and the mice induced for experimental colitis. This current study investigated whether the engineered DCs worked in humans. In addition, we also asked how zinc impacts the function of our engineered DCs because zinc is a biologically essential mineral widely included in daily supplements and has also been shown to tolerize DCs. Our data showed that the engineered DCs, derived from healthy control subjects and IBD patients, stimulated autologous naïve CD4+ T cells to express both regulatory and gut-homing molecules (gut-homing Tregs). In addition, the stimulated CD4+ T cells suppressed the proliferation of autologous effector T cells. Moreover, the addition of zinc enhanced the ability of the engineered human DCs to augment the induction of autologous gut-homing Tregs. Hence, our findings indicate zinc-treated engineered DCs are a promising novel IBD therapy.
This study was partially supported by the AAI Careers in Immunology Fellowship; the US Army Medical Research and Materiel Command grant (W81XWH-15-0240); and the GI Foundation of Loma Linda University Innovation grant (RIG-GI 681207-2967).