bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-epitopic anti-tumor T cell responses and efficient Trastuzumab-mediated ADCC promote a favorable clinical outcome in HER2+ breast cancer patients after neoadjuvant chemotherapy (165.8)
Authors: Dolcetti Riccardo , Martorelli Debora , Muraro Elena , Miolo Gianmaria , Lombardi Davide , Massarut Samuele , Perin Tiziana , Talamini Renato , Turchet Elisa , Comaro Elisa , Carbone Antonino , Veronesi Andrea , Crivellari Diana 
Published: January 2023

Abstract
The ability of drugs such as Trastuzumab and taxanes to act through immunomediated and/or immunomodulatory mechanisms suggest that anti-tumor immune responses may influence the clinical outcome of breast cancer patients. We have enumerated circulating CD8+ T cells specific for a broad spectrum of tumor-associated antigens (her2, muc-1, mammaglobin-A, trag-3, survivin, bcl-xL) in 13 patients with locally advanced breast cancer (6 HER2+ and 7 HER2-). At diagnosis, increased numbers of CD8+ T cells specific for all 13 HLA-A*0201 epitopes were observed in the whole series, with a markedly higher extent in HER2+ cases. This subset of patients retained an immunological profile similar to that of healthy women, whereas HER2- cases showed decreased circulating CD3+ T lymphocytes, higher numbers of regulatory T cells and alterations in serum cytokine levels (decreased IL-2, IL-6, and IL-8). Notably, patients with complete pathologic response (pCR), unlike those showing partial responses, retained high numbers of epitope-specific CD8+ T cells throughout the neoadjuvant chemotherapy (NC) treatment, particularly versus survivin and mammaglobin-A epitopes. Moreover, a higher efficacy of Trastuzumab-mediated ADCC in vitro correlated with the induction of pCR in HER2+ cases. These findings emphasize the crucial role of host anti-tumor T cell responses in promoting a favourable clinical outcome in the setting of neoadjuvant chemotherapy for breast cancer, particularly in HER2+ cases.
The infusion of suicide gene-modified donor T cells after hematopoietic stem cell transplantation prompts thymic renewal in adult patients by an IL-7 dependent mechanism (169.4)
Authors: Oliveira Giacomo , Vago Luca , Noviello Maddalena , Soldati Corrado , Ghio Domenico , Brigida Immacolata , Aiuti Alessandro , Lupo Stanghellini Maria Teresa , Peccatori Jacopo , Bondanza Attilio , Del Maschio Alessandro , Bordignon Claudio , Ciceri Fabio , Bonini Chiara 
Published: January 2023

Abstract
The infusion of donor lymphocytes genetically modified to express the HSV-Thymidine kinase (Tk) suicide gene after T cell-depleted Hematopoietic Stem Cell Transplanation (HSCT) provides protection against pathogens and disease recurrence, while allowing complete GvHD control. In the TK007 phase I/II clinical trial 28 adults with hematologic malignancies received purified Tk-transduced cells after T cell-depleted haploidentical HSCT, and 22 experienced a rapid immune reconstitution. Ten patients had GvHD that was controlled by ganciclovir (Lancet Oncol. 2009). Since the newly reconstituting T cells were mostly Tkneg, we hypothesized that Tk cells, which are necessary to achieve this effect, might act by prompting T cell development from graft progenitors. Patients treated with Tk cells showed prompt recovery of Tkneg naïve T cells. In particular, the CD4+ naïve subset was highly enriched in CD31+ cells, bona fide recent thymic emigrants. Accordingly, after Tk cell add-backs we documented an increase in single joint T cell Receptor Excision Circles counts and in thymic volume, as evidenced by chest CT scans. Serum levels of IL-7 markedly rose after Tk cell add-backs, suggesting that gene-modified cells may act by inducing IL-7 release, in turn supporting thymopoiesis. Taken together, our data show that the infusion of Tk cells boosts the function of adult thymus, prompting the recovery of a polyclonal, fully competent, T cell repertoire by an IL-7 dependent mechanism.
Combination of IL-2 and anti-TGF-β increases natural killer cell reconstitution after hematopoietic stem cell transplantation (169.7)
Authors: Alvarez Maite , Murphy William 
Published: January 2023

Abstract
Despite the efficacy of hematopoietic stem cell transplantation (HSCT) as a cancer therapy, cancer relapse remains a significant complication. Natural killer (NK) cells are the first lymphoid population to recover after HSCT and can kill transformed or virally-infected cells without prior sensitization. Therefore, accelerating NK cell reconstitution may improve HSCT therapy. We utilized the combination of administering the stimulatory cytokine, IL-2 concurrently with the blockade of the immunosuppressive cytokine, transforming growth factor-beta (TGF-β) as a possible therapy to accelerate NK cell reconstitution after syngeneic HSCT. Resting C57BL/6 mice were treated with daily doses of IL-2 (2x105 IU) and anti-TGF-β (120ug, clone 1D11) every other day for one week. Although combinatorial therapy did not significantly expand NK cell numbers in comparison with IL-2 monotherapy, NK cytotoxicity, as measured by the ability to lyse Yac-1 tumor cells, was significantly greater. However in a HSCT model, combinatorial therapy administered in C57BL/6 mice starting at day 11 post-HSCT did significantly increase both the percentage of activated NK cells and NK tumor lytic ability compared with IL-2 alone. Additionally, mice showed no outward evidence of toxicity during administration of therapy. Together, these results suggest that this combination regimen improves reconstitution of NK cells after HSCT which may lead to better anti-viral and anti-tumor responses.
Evolutional conservation of cytosolic antiviral activity with type I interferon mediated by the retinoic acid-inducible gene I-like receptor pathway in teleosts (170.11)
Authors: Hikima Jun-ichi , Ohtani Maki , Kondo Hidehiro , Hirono Ikuo , Jung Tae-Sung , Aoki Takashi 
Published: January 2023

Abstract
The retinoic acid-inducible gene-I-like receptor (RLR) family, one of the pattern recognition receptors (PRRs), is important for the cytosolic immune response to recognize viral RNAs as pathogen-associated molecular patterns (PAMPs). RLR family members MDA5 (melanoma differentiation-associated gene 5) and LGP2 (laboratory of genetics and physiology 2) enhance gene expression of type-I interferon (IFN-I) and inflammatory cytokines through the IPS-1 (mitochondrial adaptor IFN-β promoter stimulator-1) cascade. In this study, MDA5, LGP2 and IPS-1 were cloned from the kidney of the Japanese flounder, Paralichthys olivaceus, and their phylogenetic analyses showed their conservation to those of higher vertebrates. MDA5 and LGP2 mRNA expression were strongly up-regulated by poly I:C stimulation or VHSV infection, whereas IPS-1 mRNA expression was not. To reveal the antiviral activity of these molecules, expression vectors were constructed and used in an antiviral assay against VHSV and HIRRV using the HINAE (Hirame natural embryonic) cell line. Viral replications were visibly repressed by overexpression of the MDA5, LGP2 and IPS-1 genes. The antiviral activities were attributed to the up-regulation of type I interferon (IFN) and IFN-inducible genes (Mx and ISG15). These results indicate that MDA5, LGP2 and IPS-1 are capable of causing the inhibition of viral replication through the induction of type I IFN and IFN-inducible genes.
Analysis of the cytotoxic T lymphocyte response of MHC-defined swine to foot-and-mouth disease virus (170.14)
Authors: Patch Jared , Pedersen Lasse , Kenney Mary , Pacheco Juan , Glabman Raisa , Pandya Mital , Nielsen Morten , Buus Soren , Golde William 
Published: January 2023

Abstract
Foot-and-mouth disease (FMD) is a disease of cloven-hoofed animals that remains a threat to the livestock industry. FMD virus (FMDV) causes an acute infection characterized by fever and the formation of vesicles on the feet and tongue. This picornavirus is classified into seven serotypes and the current killed-virus vaccines provide antibody-mediated protection that is serotype specific. A next-generation vaccine that relies on non-replicating recombinant human adenovirus 5 (Ad5) has been shown to induce neutralizing antibodies. To date, the role of cytotoxic T lymphocytes (CTLs) has been marginally explored. We have shown that swine vaccinated with an Ad5 vectored vaccine that targets the CTL response exhibited greater CTL killing of MHC-matched target cells compared to swine given the aforementioned Ad5 FMDV vaccine. In two trials with the T cell vaccine, the CTL response showed limited epitope specificity by class I MHC tetramer staining. Using these assays, we now show that FMDV infection also elicits a CTL response with broader epitope specificity than that induced by vaccination. These data provide a basis for evaluating whether CTLs can protect against disease following virus challenge.
Entry of diabetogenic T cells into islets induces changes to amplify the cellular response and the entry of non-specific T cells (44.11)
Authors: Calderon Boris , Carrero Javier , Miller Mark , Unanue Emil 
Published: January 2023

Abstract
We previously showed that the early localization of activated diabetogenic T cells into the islets of Langerhans required the identification of its specific antigen presented by the resident antigen presenting cells. Instrumental in the specific localization was the presence of intra-islet dendritic cells bearing the β-cell-peptide-MHC complex. The entry of diabetogenic CD4 T cells rapidly triggered inflammatory gene expression changes in the islets and blood vessels by upregulating chemokines (CXCL9, 10 and 11) and adhesion molecules (ICAM-1 and VCAM-1). Blood vessels expressed VCAM-1 and ICAM-1. ICAM-1 was also found on β-cells. Interferon-inducible genes were upregulated as early as 8 hours post T cell transfer. These expression changes resulted in the entry of non-specific T cells. Non-specific T cells did not localize unless diabetogenic T cells were also injected. In contrast to the entry of diabetogenic CD4 T cells, the entrance of non-specific T cells required a chemokine response and VCAM-1 expression by the islets. Interferon-gamma was also important for the early gene expression changes in the islets. Mice lacking the IFN-γ receptor showed a reduced islet T cell entry and no gene or adhesion molecule changes were detected. In conclusion, these studies establish that entry of diabetogenic T cells induces a state of receptivity of islets to subsequent immunological insults.
Differential role of nucleic acid-sensing toll-like receptors in autoantibody production. (44.29)
Authors: Koh Yi , Gahan Jennifer , Fink Kathren , Silverman Gregg , Beutler Bruce , Nemazee David , Theofilopoulos Argyrios , Kono Dwight 
Published: January 2023

Abstract
SLE is associated with a diversity of autoAbs, of which some are relatively specific for SLE, whereas others are also found in other autoimmune diseases. Nucleic acid sensing-TLRs (TLR3, 7-9; NA-TLRs) through the engagement of NA-containing material alone or in immune-complexes have been shown to play a critical role in lupus pathogenesis. However it is unclear to what extent NA-TLR signaling also promotes autoAbs to self-antigens (Ags) unrelated to NA. Here, we studied the role of NA-TLRs in MRL-lpr mice using the 3d mutation that abolishes NA-TLR signaling. In 3d mice, IgG and IgM antibodies to nuclear and RNA-associated Ags were essentially completely abolished, whereas other autoAbs with potential to cross-react to NAs (cardiolipin, and β2-GP1) were reduced to a lesser extent, and Abs unrelated to NAs (desmoglein3) were unaffected. Using a novel model that addresses loss of tolerance to B cells that acquire self-reactivity after class-switch recombination, it was found that NA-TLRs did not play an essential role in this process. Absence of NA-TLR signaling reduced lymphoproliferation, splenomegaly, and glomerulonephritis, but did not affect the incidence or severity of skin disease consistent with no reduction in cryoglobulins. Thus, in the MRL-lpr model, NA-TLRs are necessary for nucleic acid-associated autoantibody specificities and glomerulonephritis, but to varying degrees for other autoAb specificities and cutaneous disease.
Titration of CD45 expression regulates sequential tolerance checkpoints during B cell development (45.2)
Authors: Zikherman Julie , Doan Kristin , Raschke William , Weiss Arthur 
Published: January 2023

Abstract
The receptor-like tyrosine phosphatase CD45 positively regulates antigen receptor (AgR) signaling by dephosphorylating the inhibitory tyrosine of the Src family kinases (SFKs). Here we take advantage of an allelic series of mice in which CD45 expression is titrated across a broad range (0-180%). Although high expression of CD45 inhibits TCR signaling, here we show that CD45 plays a purely positive regulatory role during BCR signaling. In concert with enhanced BCR signaling, mice expressing very high levels of CD45 exhibit marked loss of follicular and marginal zone B cells in a cell intrinsic manner. Although we do not see B cell loss at earlier stages of bone marrow development, we do find increasing lambda light chain usage across the CD45 allelic series suggesting that receptor editing is triggered by high CD45 expression. In the context of the IgHEL/sHEL model of B cell tolerance, such high CD45 expression transforms anergy into deletion. However, elimination of autoreactive ligand in this system fails to fully rescue survival of mature B cells in these mice. Indeed, we find that B cell survival upon exposure to BAFF is severely impaired by high CD45 expression, while low CD45 expression promotes response to BAFF. Titration of BAFF responsiveness by CD45 is cell intrinsic and correlates with BAFFR surface expression. This constitutes a novel mechanism by which B cells exhibiting hyper-responsive AgR signaling are kept in check during splenic B cell development.
A B cell subset uniquely responsive to innate stimuli accumulates in aged mice (45.7)
Authors: Hao Yi , O'Neill Patrick , Naradikian Martin , Scholz Jean , Cancro Michael 
Published: January 2023

Abstract
We have discovered a functionally distinct mature B cell subset that accumulates with age, comprising up to 30% of all mature B cells by 22 months. Despite sharing some features with other mature B cell subsets, these cells are refractory to BCR and CD40 stimulation. Instead, they respond to TLR-9 stimulation and divide maximally upon combined BCR and TLR ligation. Although similar to follicular B cells in both BLyS receptor expression and BLyS binding capacity, these cells do not rely upon BLyS for survival. Further, they are not the result of intrinsically altered B lymphopoiesis in aged bone marrow, but instead appear to be gradually generated from a small subset of mature B cells that exhaustively expand throughout the individual’s lifetime. Thus, while the magnitude of the mature primary B cell niche is maintained with age, it is increasingly populated by cells refractory to BCR-driven activation yet responsive to innate receptor stimulation. This shift may contribute to the diminished capacity for adaptive humoral responses and increased propensity for autoimmunity associated with aging.
Selective gene regulation by glucocorticoid receptor translational isoforms in T cells. (46.10)
Authors: Shin Soon Cheon , Schleimer Robert , Lu Nick 
Published: January 2023

Abstract
Glucocorticoids are indispensable in treating inflammatory diseases including asthma and hay fever. The antiinflammatory actions of glucocorticoids are mediated by the glucocorticoid receptor (GR). We previously found that alternative translation mechanisms produce multiple GR isoforms. To determine the functions of the translational isoforms of GR, we generated clones of Jurkat T cell lines expressing individual GR isoforms. Microarray analysis indicated that GR isoforms have unique gene targets. Realtime RT-PCR experiments confirmed that some genes are regulated by the GR-C but not by the GR-A isoform. These genes have a wide range of physiologic functions in T cell differentiation (eomesodermin, EOMES; and phosphoinositide-3-kinase interacting protein 1, PIK3IP1), proliferation (tumor necrosis factor superfamily member 8, TNFSF8, and B-cell translocation gene 1, BTG1), cell adhesion (junctional adhesion molecule 3, JAM3), virus-killing (interferon stimulated exonuclease gene 20kDa, ISG20), NF-B signaling (5-azacytidine induced 2, AZI2), and transcription regulation (runt-related transcription factor 2, RUNX2). Furthermore, we found that mitogens induced the GR-C but not other GR isoforms in purified CD3+ cells. Thus, GR-C selective genes may mediate glucocorticoid actions in activated T cells. These genes may also serve as biomarkers for selective GR isoform activation and provide new targets for the development of novel anti-inflammatory agents.
The expression of FcγRIIB by effector and memory CD8 T cells (46.14)
Authors: Starbeck-Miller Gabriel , Badovinac Vladimir , Harty John 
Published: January 2023

Abstract
In response to infection, antigen-specific naïve CD8 T cells proliferate and differentiate, eventually becoming long-lived memory cell populations. It has been well documented that throughout this process, CD8 T cells undergo both phenotypic and functional changes. However, the expression of FcγRIIB (CD32) by effector or memory CD8 T cells has not been reported at the molecular level. Using OT-I TCR-tg cells and OVA expressing attenuated L. monocytogenes (LM) infections, we found that CD32 mRNA was increased in memory relative to naïve populations. Surface expression of CD32 is undetectable on naive CD8 T cells, but can be observed at effector and memory time points in endogenous populations following either LM or LCMV Arm-infection. At memory, CD32+ antigen-specific CD8 T cells are CD127hiCD122hi and undergo more homeostatic proliferation relative to CD32- cells. CD32 KO antigen-specific CD8 T cells expand similarly to WT following LM challenge. However, CD32 KO cells undergo a higher degree of contraction and, thereafter, undergo less homeostatic proliferation than WT cells. These data suggest that the expression of CD32 positively correlates with the maintenance of CD8 T cells from effector to memory differentiation.
Cognate CD4+ T cells enhance CTL survival and memory programming via IL-2, CD40L and acquired pMHC-I signaling (46.16)
Authors: Sokke Umeshappa Channakeshava , Xu Shulin , Hebbandi Nanjundappa Roopa , Xiong Sidong , Jim Xiang 
Published: January 2023

Abstract
A hallmark of cellular immunity is the generation of memory CD8+ cytotoxic T lymphocytes (CTL) that escape activation-induced cell death (AICD) during the effector phase. Factors governing effector CTL survival in CD4+ T helper1 cells (Th1) that lead to functional memories are poorly understood. Here, we determined the role of Th1 cells with acquired antigen-presenting machineries on effector CTL fates. Contrary to previously known immune-regulatory mechanisms among Th1 or CTL interactions, our study establishes a novel co-operative role of cognate Th1-CTL interactions. Th1’s help mediated enhanced CTL survival, and functional memory CTL development, capable of protecting against lethal tumor challenge, via CD40L, IL-2, and acquired peptide-MHC-I signaling. Helped CTL showed survival advantages by displaying mRNA profiles similar to naïve CD8+ T cells, and increased NF-kB and Akt1 activation. In contrast, unhelped CTL underwent rapid AICD-mediated contraction through increased NFATc1 activation, and up-regulation of pro-apoptotic and down-regulation of anti-apoptotic genes known to mediate FasL- and Trail-associated apoptotic pathways. This form of Th1-CTL cooperation could explain why memory CTL generated under cognate Th1’s help show survival and recall advantages, a phenomenon frequently observed in organ transplantations, cancers, and many autoimmune and infectious diseases, and may impact effective adoptive CTL therapy of cancers.
FoxO1 represses mTOR dependent T-bet expression to facilitate CD8+ T cell memory (46.21)
Authors: Shrikant Protul , Rao Rajesh , Li Qingsheng 
Published: January 2023

Abstract
The ability of mTOR to regulate T-bet expression is central to its role in CD8+ T cell differentiation for type 1 effector functions. However, the mechanisms underpinning mTOR mediated T-bet expression are not completely understood. We demonstrate that instructional programming of naïve CD8+ (OT-1) T cells for mTOR and T-bet dependent type I effector functions, induces Akt dependent FoxO1 phosphorylation; leading to its nuclear exclusion and loss in expression of its target genes; KLF2 and CD62L. Inhibition of mTOR by rapamycin blocks FoxO1 phosphorylation, whereby increasing its expression, nuclear translocation for enhanced expression of KLF2, CD62L and for transitioning type 1 CD8+ effector to memory precursor cells. The rapamycin mediated FoxO1 expression is required to inhibit T-bet expression (mRNA, protein), switching the transcriptional profile of OT-1 cells from T-bet to Eomesodermin. Furthermore, transgenic Myr-Akt (active) or FoxO1 knockdown (siRNA) or T-bet re-expression restores type 1 effector functions in rapamycin treated FoxO1+ memory precursor OT-1 cells, indicating the essential role FoxO1 mediated T-bet repression for memory. These results reveal a novel role for FoxO1 in regulating T-bet dependent type 1effector maturation and identify duality of FoxO1 functions in regulating CD8+ T cell memory.
Inflammatory cytokines determine the susceptibility of human CD8 T cells to Fas-mediated activation-induced cell death through modulation of FasL and c-FLIP expression (46.4)
Authors: von Rossum Anna , Krall Randall , Escalante Nichole , Choy Jonathan 
Published: January 2023

Abstract
The nature of inflammatory signals determines the outcome of T cell responses. However, little is known about how inflammatory cytokines provided to human CD8 T cells during activation affect their susceptibility to post-activation cell death. We have examined and compared the effects of the inflammatory cytokines IL-12, as well as the combination of IL-1, IL-6, and IL-23 (IL-1/6/23) on the susceptibility of primary human CD8 T cells to post-activation cell death. Human CD8 T cells activated in the presence of IL-1/6/23 underwent significantly less cell death after activation as compared to those activated in IL-12. This was due to reduced susceptibility to Fas-mediated activation-induced cell death (AICD). CD8 T cells activated in IL-1/6/23 expressed less FasL and more c-FLIPs as compared to those activated in IL-12, and were also less sensitive to cell death induced by a Fas agonistic antibody. Inhibition of c-FLIP expression by siRNA increased cell death of CD8 T cells activated in both conditions. When the effect of IL-1, IL-6, and IL-23 individually was examined, IL-1 or IL-6 alone was sufficient to inhibit CD8 T cell death that occurs after activation in IL-12 while the effect of IL-23 was variable. Our findings show that the presence of IL-1 and/or IL-6 during activation of human CD8 T cells attenuates Fas-mediated AICD while IL-12 increases the susceptibility of activated CD8 T cells to this form of cell death.