bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anatomic partitioning regulates TCR-pMHC interaction and memory T cell development during early immune contraction phase
Authors: Seo Young-Jin , Jothikumar Prithiviraj , Zhu Cheng , Grakoui Arash 
Published: January 2023

Abstract
As virus is cleared, immune cells rapidly undergo contraction; however, how cell function and fate are determined during this phase is not yet fully understood. We unexpectedly discovered that during the early immune contraction phase of an acute infection with lymphocytic choriomeningitis virus, the two dimensional TCR–pMHC effective affinity of TCR transgenic P14 T cells was significantly higher for cells from the splenic red pulp (RP) than the white pulp (WP) compartment. This difference in seeing antigen was governed by FoxP3+ regulatory T cells and TGF-beta. Further, memory precursors from WP preferentially developed into long-term memory cells as compared to cells from RP, despite expression of identical cell surface markers. Our results highlight that intricate regulation of T cell function and fate is determined by anatomic partitioning during the early immune contraction phase. These findings could have an important impact on development of more efficient vaccines and T cell-targeted immunotherapy for infectious diseases, cancers, and autoimmune disorders.
MicroRNA-155 enhances T-cell trafficking and antiviral effector function in a model of coronavirus-induced neurologic disease
Authors: Dickey Laura L. , Worne Colleen , Glover Jessica , Daugherty Joshua , Lane Thomas , O’Connell Ryan M 
Published: January 2023

Abstract
Micro-RNAs (miRNAs) are non-coding RNAs that modulate cellular gene expression at the post-transcriptional level. These molecules are becoming increasingly recognized as important in helping tailor T-cell responses following viral infection. We therefore sought to examine the functional role of miR-155 in a model of viral-induced demyelination. Intracranial injection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in an acute encephalomyelitis followed by an immune-mediated demyelinating disease. Compared to wild-type mice, JHMV-infected mice deficient in miR-155 (miR-155−/−) developed delayed but exacerbated disease concomitant with increased morbidity/mortality, weight loss, and spinal cord demyelination. In addition, miR-155−/− mice had decreased total and virus-specific CD4+ and CD8+ T-cell accumulation within the CNS during the acute phase of disease. Furthermore, IFN-γ and TNF-α production, as well as and cytolytic function, were impaired in CD8+ cells from miR-155−/− mice. These results identify miR-155 as a key mediator of disease development and recovery in a model of virus-induced neurological disease.
Identification of CD112R as a new coinhibitory receptor for CD112
Authors: Zhu Yuwen , Paniccia Alessandro , Schulick Alexander C , Koenig Michelle R , Edil Barish H 
Published: January 2023

Abstract
Cancer immunotherapy has had great success in the clinical setting, with immunomodulating agents targeting immune checkpoints (including CTLA-4 and PD-1) leading the way. However, the overall response rate is still low and its effectiveness on certain tumors is disappointing. Therefore, identifying novel T cell checkpoints is critically needed, for new treatment strategies. TIGIT and CD226 emerge as a novel T cell cosignaling pathway with the potential of cancer immunotherapy. CD226 and TIGIT serve as a costimulatory receptor or a coinhibitory receptor respectively for the ligand CD155 (PVR) and CD112 (PVRL2). In this study, we identified CD112R as a missing coreceptor of this important PVR-like network. CD112R, also a member of the PVR family, is preferentially expressed on T cells and inhibits TCR-mediated signal. We further identified that CD112, widely expressed on antigen-presenting cells and tumor cells, is the ligand for CD112R with high affinity. CD112R competes with CD226 to bind CD112. Disrupting the CD112R/CD112 interaction enhances human T-cell response. Thus, our studies identify CD112R as a novel checkpoint for human T cell, and modulating this pathway will offer new targets for future immunotherapy.
Defining the role of Tim-3 in T cells
Authors: Avery Lyndsay , Kane Lawrence P 
Published: January 2023

Abstract
Chronic viral infection and the tumor microenvironment are two settings in which persistent immune stimulation can occur. Under such conditions, T cell activation becomes downregulated, likely in order to reduce immune pathology, resulting in a phenotype known as T cell ‘exhaustion’. Functionally exhausted T cells are characterized by reduced cytokine production, proliferative capability, and cytotoxic activity, with a corresponding expression of checkpoint receptors, including PD-1, CTLA-4, LAG-3 and Tim-3. While PD-1, CTLA-4, and LAG-3 have known mechanisms for reducing T cell effector function, the intrinsic effects of Tim-3 on T cell activation are largely unknown. In fact, recent evidence reveals divergent effects of Tim-3 in various infectious models. Data from our lab indicate that Tim-3 can enhance acute TCR signaling, while much of the existing literature associates Tim-3 expression with diminished effector function. Current approaches to study Tim-3 require persistent antigen stimulation or ectopic expression. We have developed a novel mouse model where the expression of Tim-3 is induced in vivo by Cre-mediated recombination. We hypothesize that inducible Tim-3 expression may cause T cells to become dysfunctional earlier by enhancing the initial response to stimulation. Using this model, we have found that the presence of Tim-3 enhances T cell activation after acute in vitro stimulation. We are currently testing how induction of Tim-3 will affect responses to a murine model of chronic viral infection, LCMV-clone13. Results from this study will address knowledge gaps about the effects of Tim-3 on T cells and will have practical applications in both chronic viral infection and cancer immunotherapy.
Cbl-b deficiency renders T cells resistant to PD-L1/PD-1 mediated suppression
Authors: Fujiwara Mai , Anstadt Emily J , Clark Robert B 
Published: January 2023

Abstract
The PD-L1/PD-1 pathway is a critical regulator of T cell responses that has become a significant focus in cancer immunotherapy. Cbl-b is an E3 ubiquitin ligase that regulates many aspects of T cell activation. In humans, polymorphisms in the CBLB gene are associated with autoimmunity. Cbl-b deficient (Cbl-b−/−) mice demonstrate spontaneous autoimmunity and enhanced anti-tumor T cell responses. Thus, there is now great interest in manipulating Cbl-b to enhance anti-tumor T cell responses.
We now report that, in contrast to WT T cells, in vitro TCR-stimulated proliferative responses of Cbl-b−/− CD4+ and CD8+ T cells are not suppressed by a recombinant PD-L1 fusion protein (PD-L1 Ig) (% suppression in CD4+: WT 40%, Cbl-b 0%, p&lt;0.01; in CD8+: WT 32%, Cbl-b 5%, p&lt;0.05). Moreover, IFN-γ production of Cbl-b−/− CD4+ T cells is less suppressed by PD-L1 Ig than that of WT cells (% Suppression: WT 68%, Cbl-b 20%, p&lt;0.0001). Importantly, PD-1 expression is comparable between Cbl-b−/− and WT T cells. To confirm this PD-L1 resistance in vivo, we used a model of B16 melanoma in which liver metastases develop only when PD-L1/PD-1 immune regulation is functionally intact. We confirmed that WT mice develop numerous liver metastases which are significantly reduced by anti-PD-1 antibody treatment. Strikingly, Cbl-b−/− mice develop only rare liver metastases even in the absence of anti-PD-1.
In sum, we report for the first time that Cbl-b−/− T cells are resistant in vitro and in vivo to suppression by PD-L1/PD-1. Our finding of Cbl-b−/− T cell resistance to PD-L1/PD-1-mediated inhibition broadens our understanding of Cbl-b’s role in autoimmunity and suggests a new mechanism by which manipulation of Cbl-b function may lead to enhanced anti-tumor T cell responses.
Identifying Fas/CD95 non-apoptotic signaling pathways associated with T cell differentiation
Authors: Thomas Stacy K , Ouyang Claudia , Cruz Anthony C , Klebanoff Christopher A , Yamamoto Tori N , Chan Francis K , Mocarski Edward S , Roback Linda , Restifo Nicholas P , Siegel Richard M 
Published: January 2023

Abstract
Fas (CD95, TNFRSF6), a member of the TNF cytokine superfamily, triggers apoptosis through recruitment of FADD and Caspase 8. However, Fas can also induce other responses besides cell death, including costimulating T-cell activation and promoting tumor cell growth and metastasis. We have found that Fas accelerates the differentiation of naïve T cells into effector memory cells. In vivo, Fas deficiency is known to cause autoimmunity, which has been attributed to a lack of Fas-induced cell death. Interestingly, we observed that palmitoylation-defective Fas C194V transgenic mice, in which Fas cannot induce apoptosis but can signal for differentiation, did not present with autoimmunity. This led us to hypothesize that non-apoptotic Fas signaling plays a role in autoimmunity and investigate the signaling pathways underlying Fas-induced differentiation.
Primary T cells lacking FADD or Caspase 8 and cells treated with caspase inhibitor z-VAD did not differentiate suggesting that Fas-induced T cell differentiation depends on FADD, Caspase 8 and caspase activity. Moreover, we observed that cells undergoing Fas-induced differentiation had increased pAkt and pS6, and that Akt inhibition blocked differentiation. Although Fas does not directly activate Akt, activation of this pathway by Fas in the context of T cell activation is dependent on IL-2, suggesting that instead of directly activating Akt, Fas potentiates the IL-2 initiated PI3K/Akt pathway. Together, our data show that Fas potentiates the induction of PI3K/AKT signaling by IL-2 to accelerate naïve T cell differentiation via a FADD and Caspase 8 dependent mechanism.
Fibroblastic reticular cells of the secondary lymphoid organ suppress T cell activation via COX2 mediated PGE2 secretion.
Authors: Yu Miao , Guo Gang , Xiao Wei , Cui Yan 
Published: January 2023

Abstract
Accumulating evidence demonstrates that fibroblastic reticular cells (FRCs) in the T cell zone of the secondary lymphoid organs (SLO), characterized as CD45− gp38+CD31− cells, play an important role in maintaining T cell tolerance via presenting peripheral tissue–restricted antigens (PTAs) and/or interferon-induced nitric oxide during productive immunity. Here, using FRCs harvested from naïve mice, we revealed that FRCs also inhibit T cell activation via a soluble factor, independent of the aforementioned mechanisms. Specifically, FRCs suppressed CD3/CD28-ligation mediated or antigen induced antigen-specific T cell activation. This FRC-imposed suppression was demonstrated as (1) reduced Zap-70 phosphorylation and Calcium-flux within 30 minutes of TCR-ligation, (2) inhibited upregulation of surface CD69 and CD44 expression and downregulation of CD62L 6–14 hours post-activation, and (3) suppressed T cell effector cytokine production and proliferation. Further studies demonstrated that our observed inhibition of T cell activation by FRC is at least partially contributed by cyclooxygenase-2 (COX-2) mediated production of prostaglandin E2 (PGE2) because COX-2 inhibitor partially reversed FRC mediated inhibition. ELISA results confirmed high production level of PGE2 by FRC (~ 10 – 50ng/ml), at which level T cell activation is greatly suppressed. Taken together, our study illustrated another previously unrecognized mechanism of FRCs in maintaining T cell tolerance, which underscores the crucial role of FRCs in peripheral tolerance and immune regulation. The potential molecular mechanism by which the COX2-PGE2 pathway is activated in FRCs under physiological condition will be discussed.
Novel mechanism in autoimmune regulation by S-nitrosoglutathione
Authors: Won Jeseong , Saxena Nishant , Samuvel Devadoss J. , Choi Seungho , Singh Avtar K. , Singh Inderjit 
Published: January 2023

Abstract
Nitric oxide (NO) plays a pivotal role in pathogenesis and control of autoimmune disease which is caused by abnormal activation of T helper (Th) cells. Under disease conditions of experimental autoimmune encephalomyelitis (EAE), we observed that different subsets of Th cells expressed different levels of NO synthesizing enzymes (nNOS, iNOS, and eNOS). Notably, Th17 cells exclusively expressed high levels of iNOS and its genetic ablation resulted in increased Th17 activation and IL-17 expression but decreased activation of specific subset of regulatory T (CD4+CD25+FOXP− Treg) cells and IL-10 expression in EAE. S-nitrosoglutathione (GSNO) is a physiological NO carrier molecules that mediates variety of NO signaling via trans-S-nitrosylation mechanisms. In EAE, GSNO treatment decreased the disease severity and activation/effector function of Th17 while it increased CD4+CD25+FOXP− Treg activation/effector function. Moreover, the reduced activation/effector function of Th17 by adaptive transfer of GSNO-induced CD4+CD25+FOXP− Tregs suggest that CD4+CD25+FOXP− Treg may be the effector cells antagonizing Th17 in response to iNOS/NO/GSNO. The cellular levels of GSNO is regulated by its catabolic enzyme GSNO reductase (GSNOR). In EAE, both Th17 and of CD4+CD25+FOXP− Treg expressed high levels of GSNOR and pharmacological inhibition of GSNOR or genetic ablation of GSNOR resulted in abrogation of Th17 activation/effector function while activating CD4+CD25+FOXP− Treg. In summary, this study suggest the iNOS/NO/GSNO-inducible CD4+CD25+FOXP− Treg cells as the potential feedback regulator of Th17 and GSNOR as the potential therapeutic target for Th17 and CD4+CD25+FOXP− Treg mediated autoimmune disease.
CD40L signaling from CD8+ T cells confers protection against influenza infection
Authors: Tay Neil Q , Lee Debbie C P , Chua Yen Leong , Prabhu Nayana , Kemeny David Michael 
Published: January 2023

Abstract
CD40L is a principal mediator of a large range of humoral and cellular responses and CD40L-mediated licensing of dendritic cells is known to be necessary for the generation of robust effector and memory CD8+ T cell responses. Although the effects of CD40L when expressed on CD4+ T cells are well studied, its role when expressed on CD8+ T cells remain unclear. We have previously reported that CD40L signaling mediates the induction of IL-12 p70 production in dendritic cells when expressed by CD8+ T cells. However, the role and importance of this mechanism in CD8+ T cell responses during an infection are not known. To investigate the function of CD40L when expressed on CD8+ T cells in an in vivo mouse model, we crossed OT-I CD8+ T cell receptor transgenic mice with CD40L−/− mice to generate OVA-specific CD8+ T cells that are unable to expressed CD40L. By transferring CD8+ T cells from these mice into CD40L-competent mice and using a strain of influenza that expresses the OVA epitope recognized by OT-I CD8+ T cells, we were able to create an influenza mouse model where CD40L signaling is absent only on the responding CD8+ T cells. Our analysis indicates that CD40L signaling by CD8+ T cells confers protection against influenza infection and that this is likely dependent on the ability of CD8+ T cells to induce IL-12 p70 production in a CD40L-dependent manner.
mTOR activity is necessary for cytokine-mediated TBET expression in TLR-stimulated B cells
Authors: Myles Arpita , Naradikian Martin S , Cancro Michael P 
Published: January 2023

Abstract
A recently described subset of B cells – called age associated B cells (ABCs) – is characterized by the increased expression of TBET. While known to be particularly relevant in the settings of aging and autoimmunity, the cell intrinsic signaling pathways leading to the development of the ABC phenotype are not well-characterized. Since the mTOR pathway is a known regulator of TBET expression in other cell types, we examined its role in B cells stimulated with TLR agonists. Our findings indicate that TLR9 (CpG) or TLR7 (Cl097) ligands alone activate mTOR, as evidenced by S6 phosphorylation, but do not yield robust TBET upregulation without concomitant cytokine stimulation. Indeed, IFNγ and IL-21 induced TBET expression is lost in response to rapamycin (mTOR inhibitor) treatment. This indicates that mTOR activity is necessary but not sufficient for TBET expression. The implication that mTOR could be a node for integration of signals downstream of TLR and cytokines to regulate TBET expression in B cells merits further investigation, and might provide novel mechanistic insights into various B cell differentiation programs.
Macrophage lipid accumulation is regulated by substrate stiffness
Authors: Leifer Cynthia A , Gruber Erika , Stelzer Sandra , Erlich Emma , Sinha Siddhartha 
Published: January 2023

Abstract
Atherosclerosis is characterized by the accumulation of lipid-laden macrophage foam cells within the vessel wall, formation of a plaque, and changes in tissue stiffness from soft near the necrotic core to stiff near the fibrous cap. The mechanisms governing foam cell formation are not well understood, but recent studies demonstrate that cells probe and respond to the physical properties of their surroundings. Stiffness regulates differentiation and function of mesenchymal stem cells and endothelial cells, yet until recently, its role in immune cell function has been largely unexplored. Our lab, and others, has found that substrate stiffness regulates murine macrophage cytokine secretion and phagocytic activity. Because macrophages accumulate near the soft necrotic core where there is abundant lipid, we hypothesized that macrophages on softer surfaces would exhibit enhanced lipid accumulation. To investigate this, we cultured murine macrophages on functionalized tunable polyacrylamide gels that model physiologically relevant stiffnesses. We then used a combination of flow cytometry and immunofluorescence microscopy to show that softer substrate stiffness results in more accumulation of the model lipid, oleic acid, as well as acetylated low-density lipoprotein in macrophages. Transcriptomic analysis identified up- or down-regulated genes in macrophages in response to increased substrate stiffness, including genes implicated in atherosclerosis and lipid metabolism. Together, these data demonstrate that lipid accumulation by macrophages is regulated in part by substrate stiffness and mechanotransduction signaling and reveal a potential link between changes in tissue stiffness and macrophage lipid accumulation.
SHP-1 impacts mitochondrial function in cellular metabolism
Authors: Martinez Hunter , Martinez Ryan , Evavold Brian D 
Published: January 2023

Abstract
SHP-1 is a protein tyrosine phosphatase (PTP) that plays critical roles in many hematopoietic cell signaling pathways. For T cells, initial investigations elucidating the role of SHP-1 show its involvement as a negative regulator by dephosphorylating Lck and ZAP70, two kinases instrumental in early T cell activation. Despite its role as a negative regulator, minimal differences were observed in proliferation of SHP-1 −/− CD4 T cells when compared to WT cells. To investigate this disparity metabolism was studied, as cellular division is highly reliant upon energy allocation. Analysis of T cell glycolysis indicated defects in the absence of SHP-1 and that at maximal respiration SHP-1 plays a role in maintaining energy production and is necessary for optimal mitochondria functionality. Furthermore, in the absence of SHP-1 there is approximately 20% reduction in mitochondrial functionality in both naïve and activated CD4 T cells. This goes in parallel with a noted decrease in the amount of ATP in SHP-1 −/− CD4 T cells. Therefore, SHP-1 plays critical roles in T-cell cellular metabolism in addition to being a key regulatory phosphatase.
Transmembrane TNF–TNFR2 Antagonizes TH17 Differentiation by Promoting Il2 Expression
Authors: McKarns Susan C , Miller Patrick G 
Published: January 2023

Abstract
While IL-17 is critical for host defense, its overabundance promotes autoimmunity. IL-2 represses TH17 differentiation, but a role for tumor necrosis factor (TNF) in this process is not well defined. TNF binds TNF receptor 1 (TNFR1) and TNFR2 to stimulate opposing signaling cascades. Whereas sTNF signals through TNFR1, tmTNF preferentially activates TNFR2. We have previously demonstrated reduced IL-2 production in TNFR1−/− TNFR2−/− double knockout CD4+ T cells. To further explore the mechanism by which TNF regulates IL-2 production, we generated TNFR1−/−, TNFR2−/−, and TNFR1−/− TNFR2−/− 5C.C7 TCR Il2-GFP mice to study Il2 transcription at the single cell level. Our findings indicate that CD4+ T cell–intrinsic tmTNF/TNFR2 stimulates Il2 promoter activity and Il2 mRNA stability. Pharmacological blockade of TNF in wild-type C57BL/6 mice and tmTNF Foxp3-GFP mice also demonstrated tmTNF/TNFR2-mediated augmentation of Il2 expression. We further report elevated expression of TNFR2 on the surface of TH17-polarized CD4+ T cells and show that tmTNF/TNFR2, but not sTNF/TNFR1, inhibits TH17 differentiation. Under TH17-polarizing conditions, elevated IL-17 production by TNFR2-knockout CD4+ T cells correlated with increased STAT3 activity and was prevented by exogenous IL-2. We conclude that increased IL-2 production in response to CD4+ T cell–intrinsic tmTNF/TNFR2 signaling is sufficient to inhibit TH17 differentiation in a Foxp3-independent manner.
The Neurotrophic Factor Neuritin Maintains and Promotes the Function of Regulatory T cells in Autoimmunity and Cancer
Authors: Barbi Joseph J , Vignali Paolo D. A. , Yu Hong , Pan Fan , Pardoll Drew 
Published: January 2023

Abstract
Regulatory T cells (Tregs) enforce immune homeostasis and self-tolerance and inhibit both natural and induced anti-tumor immunity. Consequently, there is considerable interest in therapeutic Treg enhancement or blockade to treat inflammatory/autoimmune diseases and cancer, respectively. Targeting Tregs requires a comprehensive understanding of the factors important for their maintenance, differentiation and function. Here we report that neuritin, a conserved, gpi-anchored molecule important for the development, survival and function of neurons, is highly expressed by induced and natural Tregs. Furthermore, neuritin expression was found to promote the maintenance of the Treg pool by stabilizing Foxp3 expression and promoting the persistence of these cells. Knockout of the neuritin gene in Tregs or anti-neuritin antibody treatment mitigated both Treg-dependent inhibition of colitis and resolution of experimental autoimmune encephalitis. Also, tumors grew poorly in Nrn1−/− mice, which mobilized more robust anti-tumor immunity than their wild type litter mates evidenced by elevated IFNgamma production and reduced PD1 expression. Importantly, we also found that in Tregs, neuritin expression was closely linked to the functional differentiation of Tregs into an activated, peripheral tissue-homing phenotype. As such, neuritin deficiency resulted in an imbalance between “central”- and “effector”-like Treg populations and functions. These findings characterize this neurotrophin as a hitherto unappreciated immunoregulatory molecule and a potential target for therapies aimed at the fine-tuning of Treg function in cancer and inflammatory/autoimmune diseases.