bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole-body irradiation impairs naïve CD4 T cell function
Authors: Kannan Shravan Kumar , Turner Ti-ara , Heidarian Mohammad , Shahi Shailesh , Kim Caleb , Griffith Thomas , Harty John , Mangalam Ashutosh , Badovinac Vladimir 
Published: November 2024

Abstract
Advancements in nuclear power and radiotherapy have expanded new avenues for whole-body irradiation (WBI) to humans, urging the need to understand its impact on immune cells. While most studies focus on the numerical recovery of naïve T cells post-WBI, less is known regarding its impact on their function. We subjected B6 SPF mice to 0/5Gy doses of WBI and used I-Ab tetramer enrichment to track the recovery of naïve CD4s of different antigen specificities post WBI. The number of MOG40 specific CD4 T cells is diminished 10 days post-irradiation (DPR), and recovered by 40DPR. To test if they are able to induce EAE post-WBI, we administered MOG+CFA, followed by pertussis toxin (PTX). The 10DPR mice showed delayed EAE development, likely due to diminished MOG40 naïve precursors. Interestingly, the 40DPR mice potentiated EAE compared to the 0Gy mice, evidenced by increased CD4 priming in the dLN, and spine infiltration. While WBI-mediated CD4 T cell-intrinsic changes could contribute to the timing/severity of EAE, T cell-extrinsic factors could also influence disease. To test if WBI compromises the blood-brain barrier (BBB) and facilitates EAE progression, EAE is induced in +/-WBI mice without PTX. In the absence of PTX, 0Gy mice did not develop EAE, while the 10- and 40DPR mice developed EAE suggesting BBB impairment. Overall, WBI directly impacts the number and function of autoreactive CD4 T cells, while helping them enter the spine by changing the environment.
Delineation of naïve CD8+ T cell loss and reconstitution following exposure to sublethal whole-boy irradiation
Authors: Heidarian Mohammad , Kumar Kannan Shravan , Swanson Whitney , Griffith Thomas , Harty John , Badovinac Vladimir 
Published: November 2024

Abstract
While the immunosuppressive effect of ionizing radiation (IR) is commonly used as a conditioning regimen of hematopoietic stem cell transplants, delayed immune reconstitution, mainly lymphocytes, remains a leading cause of morbidity and mortality. We have previously shown that memory CD8+ T (TMEM) lymphocytes, potent mediators of anti-tumor and intracellular re-infections, are permanently lost and exhibit subpar functionality long after sublethal whole-body irradiation (WBI). However, the long-term impact of WBI on naïve CD8+ T (TN) cells, a key component of immune response to new intracellular pathogens, remains poorly understood. Using P14 LCMV immune chimeric mice, we observed that although TN cells are more susceptible to radiation-induced cell loss than bona-fide TMEM cells, the number of TN cells gradually recovered in a thymus-dependent manner. Profiling the T cell receptor (TCR) beta-chain repertoire within total TN cells revealed altered TCR clonotype composition and diversity in lymphoreplete irradiated hosts. Additionally, the numerical recovery of TN cells was concomitant with an increased representation of virtual memory phenotype (CD11ahi, CD49dlo, CD62Lhi) in total and GAP5041-48, B8R20-27, and GP33-41 epitope-specific CD8+ T cells. Together, these data demonstrate lasting numerical and phenotypical changes to the TN compartment, which may influence the breadth of primary immune responses to newly encountered antigens or infections.
dsiRNA Inhibition of Tetraspanin-1 gene in Trichomonas vaginalis: Effect on host immune responses
Authors: Kucknoor Ashwini , Hancock Erin 
Published: November 2024

Abstract
Trichomonas vaginalis (TV) is a common sexually transmitted infection, that causes Trichomoniasis. Little research is done to understand the mechanisms involved in TV’s communication with host cells. TV can communicate with host cells via specialized extracellular vesicles known as exosomes. Exosomes are membrane-bound, endocytic vesicles (MVBs) that are used to traffic proteins and genetic material, to neighboring cells. The sorting of proteins in the MVBs is facilitated by a group of proteins known as tetraspanins. The tetraspanins take part in a wide range of functions. TV genome contains several tertaspanin genes. Tetraspanin-1 (TSPAN-)1 is known to be lining the MVBs when TV attaches to host cells. To understand the role of TSPAN-1 gene in eliciting host immune responses, we designed custom dsiRNA primers to inhibit the expression of TSPAN-1 in TV parasites and study its effect on TV exosome formation and changes in TLR gene expression in host epithelial cells. We successfully inhibited TSPAN-1 gene in Trichomonas. The transfected parasites when exposed to host epithelial cells, resulted in reduced number of exosomes formed. In addition, TLR 2 gene expression was downregulated, while TLR 9 was upregulated when TSPAN-1 inhibited TVs were exposed to epithelial cells. TLR 4 gene expression, however, was not altered suggesting that tetraspanin-1 in the Trichomonas play a role in host -pathogen interactions and altering the host-immune responses in TV pathogenesis.
Advancing Cryptococcal Immunity: The Indispensable Role of Batf3-cDC1 in Th1 Response Regulation
Authors: Xu Jintao , Hissong Rylan , Bareis Rachel , Creech Arianna , Goughenour Kristie , Freeman Christine , Olszewski Michal 
Published: November 2024

Abstract
Cryptococcus neoformans, a fungal pathogen, is responsible for severe meningoencephalitis and approximately 200,000 annual fatalities worldwide. While type I conventional dendritic cells (cDC1) are vital for generating adaptive immunity against intracellular pathogens and tumors, their role in defense against C. neoformans remains unclear. Utilizing a mouse model adept at restricting cryptococcal infection, we identified a unique transcriptional profile in the cDC1 subset, characterized by an enhanced upregulation of T-cell recruitment and activation pathways. Using Batf3-/- mice, which lack the cDC1 population, we assessed the function of these cells in antifungal immunity. The absence of Batf3-dependent cDC1 critically impairs the host's ability to mount an effective immune response against the fungal pathogen, particularly in the lung and brain. We found reduced CD4+ T cell accumulation and diminished interferon-gamma production in BATF3-/- mice, underlining cDC1's role in driving robust Th1 responses. Furthermore, Batf3-/- mice exhibited significantly weakened fungicidal activity and compromised fungal containment. This study sheds light on the vital role of a specific DC subset, Batf3-dependent cDC1, in shaping protective Th1 responses necessary for the clearance of cryptococcal infections. Our findings highlight the potential of targeting cDC1 pathways in designing interventions against C. neoformans, offering new avenues in the fight against deadly fungal pathogens.
Targeting the NS4b Antigen of West Nile Virus to the Endocytic Receptor DEC-205 to Stimulate Protective T Cell Responses to West Nile Virus Encephalitis
Authors: Herzler Joshua , Durrant Douglas , Hernandez Valeria 
Published: November 2024

Abstract
West Nile Virus (WNV), the primary cause of mosquito-borne neuroinvasive disease in the US, poses a significant public health threat without an approved human vaccine. DCs are pivotal in orchestrating immune responses, dictating antigen-specific effector T cell activation or tolerance based on their maturity. The endocytic receptor DEC-205, expressed by specific DC subsets, facilitates antigen uptake, processing, and cross-presentation, initiating an effective T cell response. Studies highlight DEC-205+ DCs within the CNS in reactivating antiviral effector T cell responses, restricting WNV replication, and mitigating immunopathology. We propose targeting antigens to these DCs to enhance antiviral immunity against WNV within the CNS, fusing antigens to DEC-205-specific monoclonal antibodies (mAbs). A DEC-205-targeted hybrid antibody will be developed, conjugating the WNV NS4b immunodominant peptide to a DEC-205 mAb. Subsequent purification will precede testing therapeutic efficacy in a murine WNV encephalitis model. Delivering the aDEC-205 hybrid mAb with DC maturation stimulus (poly I:C), we will assess co-stimulatory molecule expression (CD40, CD80, and CD86) on DCs and evaluate T cell activation through activation marker expression and cytokine production. This research introduces a vaccination approach against West Nile Virus encephalitis, leveraging targeted antigen delivery to DEC-205+ DCs, offering insights into potential therapeutic and preventive strategies.
ISGylation during Human Parainfluenza Virus Type 3 Infection
Authors: Miller Lindsay , Mehari Liyon , Hoffman Michael , Bose Santanu 
Published: November 2024

Abstract
Human parainfluenza virus type 3 (HPIV3) causes lower respiratory illnesses such as pneumonia or bronchiolitis in infants, young children, and the immunocompromised. HPIV3 associated airway inflammatory diseases manifest as a result of host mediated exaggerated inflammatory response, though limited knowledge exists regarding HPIV3-host interactions. ISGylation is a ubiquitin- like modification that plays a role in controlling various aspects of virus infections and is the process by which Interferon stimulated gene 15 (ISG15) is conjugated to target proteins by ubiquitin-like conjugating enzymes. Several respiratory viruses induce ISGylation, and this event has been shown to modulate virus-host interaction, typically leading to a restriction in viral replication. Because of its antiviral property, some viruses possess proteins which restrict ISGylation. So far, the role of ISGylation during HPIV3 infection has not been established, and as such, no HPIV3 viral protein has been identified in regulating ISGylation. We show that HPIV3 can induce ISGylation in both myeloid immune (macrophages) and non-myeloid stromal (epithelial cells) cells. Our studies also show HPIV3 encoded non-structural C protein inducing ISGylation in cells expressing the C protein. The role of ISGylation during HPIV3 infection and the mechanism by which viral C protein induces ISGylation will be discussed.
Molecular targeting of Bcl-xL during chemotherapy-induced tumor dormancy can inhibit breast cancer relapse
Authors: Koelsch Nicholas , Gupta Kinjal , Neely Victoria , Harada Hisashi , Manjili Masoud 
Published: November 2024

Abstract
Breast cancer (BCa) mortality is mainly due to distant recurrence of the disease associated with the establishment of tumor dormancy following initially successful treatment of early-stage breast cancer. Current clinical practice for cancer survivors is a “wait and watch” approach without any therapeutic or relapse preventing interventions, except for ER-positive BCa patients who receive hormone therapy, yet remain at risk of tumor recurrences. In attempt to identify a molecular target in dormant tumor cells, we discovered upregulation of Bcl-xL in chemotherapy-induced dormant tumor cells. To target such survival pathway in FVBN202 transgenic mouse model of neu-overexpressing breast cancer, we first established tumor dormancy by means of a low dose immunogenic chemotherapy (FAC, 5-FU + Adriamycin + Cyclophosphamide) of the neu-overexpressing mouse mammary carcinoma (MMC) while using a specific inhibitor of Bcl-xL, A-1331852. Such combination therapy in vitro resulted in the inhibition of chemotherapy-induced tumor relapse. In addition, selective knockdown of Bcl-xL in MMC by means of shRNA prevented relapse of chemotherapy-induced dormant tumor cells. Our findings suggest tumor-targeted delivery of A-1331852 during chemotherapeutic treatment of early-stage breast cancer for the prevention of distant recurrences of the disease.
B Cell Maturation Antigen Inhibits an Inflammatory Role of Testosterone in Experimental Autoimmune Encephalomyelitis in C57BL/6 mice.
Authors: Kumar Gaurav , Ko Rose , Bhatt Neal , Axtell Robert 
Published: November 2024

Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Sex influences both the incidence and prognosis of MS, with the disease more prevalent in women than men. Yet, men experience a more severe disease compared to women. The interplay of immune cells, hormones, and genetics may contribute to these phenomena. In experimental autoimmune encephalomyelitis (EAE) model of MS, there are no discernible effects of sex hormones in C57BL/6 mice. However, we now report an unexpected role of BCMA in controlling an inflammatory function of testosterone in C57BL/6 mice during EAE. BCMA, a cytokine receptor with established effects on B cells, was previously shown to attenuate EAE. We now show sex differences in EAE in BCMA-deficient C57BL/6 mice. Like other reports, we show no differences in the severity of EAE in male and female BCMA+/+ mice. However, the BCMA-/- males had significantly increased paralysis and CNS inflammation compared to BCMA-/- females. Remarkably, castration of BCMA-/- males significantly reduced EAE compared to sham controls, which was not observed in the BCMA+/+ males. In addition, we found that administration of testosterone pellets elevated EAE in male and female BCMA-/- mice. Previous EAE studies have shown a protective effect of testosterone in mice with genetic backgrounds other than C57BL/6. We now show a novel function for BCMA, where it inhibits a paradoxical inflammatory role for testosterone during EAE in C57BL/6 mice.
IgE Neutralization Reverses Trimellitic Anhydride-Induced Urticaria in Humanized CD34+ Mice
Authors: Yi Hao 
Published: November 2024

Abstract
Urticaria is a significant challenge affecting the quality of life for a substantial population worldwide, manifested by the sudden appearance of wheals, erythema, and pruritus triggered by allergic reactions, infections, or physical stimuli. Immunoglobulin E (IgE) plays a pivotal role in urticaria pathogenesis by mediating mast cell accumulation and degranulation to regulate the release of inflammatory mediators such as histamine.
We developed a humanized CD34+ mouse model of urticaria by sensitizing the depilated skin topically with Trimellitic anhydride (TMA) on four occasions, with anti-human IgE as the positive control. Four consecutive days after the final sensitization, we observed and scored animal ear conditions, and enumerated scratching frequency. Additionally, mast cell counts in the skin and ear were evaluated.
TMA-sensitized animals exhibited increased ear thickness, scoring, scratching frequency, and mast cell numbers in both skin and ear compared to normal animals. Toluidine blue staining confirmed a significant rise in mast cell numbers in TMA-sensitized mice, correlating with elevated histamine levels.
Treatment with anti-human IgE ameliorated urticaria symptoms, showcasing comparable ear thickness, mast cell numbers in the ear and skin, and scratching frequencies to the normal animals. Our findings indicate that IgE neutralization effectively reversed TMA-induced urticaria in humanized CD34+ mice.
Regulation of MHC II by OPTN, a novel regulator of MARCH1 via mTOR/AKT2/STAT3 pathway ameliorates severe outcomes during herpesvirus infection.
Authors: Kadam Rashmi , Shukla Deepak 
Published: November 2024

Abstract
Protective immune responses elicited by primary activation of CD4+ T cells via dendritic cells is an essential requirement to evade herpesvirus infections. Optineurin (OPTN), a selective autophagy adaptor protein, is a crucial host restriction factor for herpes simplex virus (HSV) infection. We observed a significant reduction in the basal level of MHCII expression in OPTN–/– DCs accompanied by a concomitant decrease in CD4+ T cell counts in OPTN–/– mouse model. We hypothesize that abrogation of antigen presentation via MHCII in DCs weakens adaptive immune responses, leading to severe HSV1 infection. In this study, we elucidate the mechanism of OPTN-mediated down-regulation of MHCII via AKT/mTOR/STAT3 pathway. Mechanistically, OPTN induces activation of mTORC2 sequentially upregulating AKT2 which adversely affects the activation of mTORC1 and STAT3 protein. This could be attributed to the dynamic interplay between AKT1 and AKT2. Our findings provide novel insights into how the absence of OPTN downregulates AKT2 and triggers STAT3 activation. Furthermore, aberrant activation of STAT3 influences transcriptional activity of MARCH1(an E3 ubiquitin ligase) via IL10. MARCH1 mediates ubiquitination of MHCII resulting in the reduction of MHCII expression in OPTN–/– and AKT2–/– DCs. This study represents the first comprehensive delineation of the signaling pathway involved in the regulation of MHCII, shedding light on the intricate interplay between OPTN, AKT, mTOR, STAT3, and MARCH1.
VelociT mice genetically humanized for the T cell receptor, MHCI/II and CD4/CD8 serve as a promising platform for studying HLA-restricted T cell responses in multiple inflammatory settings.
Authors: Tay Amanda , Herbin Olivier , Farrales Pamela , Moore Michael , Macdonald Lynn , Sleeman Matthew , Orengo Jamie 
Published: November 2024

Abstract
Mouse models of T cell-mediated immune diseases are routinely used as preclinical models for investigation of human diseases. However, it is challenging to recapitulate HLA-restricted human T cell immune responses in mice. We previously developed VelociT mice by replacing the mouse genes in the variable regions of TCRab, along with the extracellular domains of the coreceptors CD4 CD8 with corresponding human sequences, and swapped the ectodomains of mouse major histocompatibility complex class I and II proteins for the human sequences of HLA-A2 and HLA-DR2, respectively. Here, we aimed to study the development of T-cell mediated responses in VelociT mice including CD4 T cell mediated autoimmune disease, CD8 T cell mediated target killing, and allogeneic skin graft rejection. We demonstrated that VelociT mice immunized with MOG35-55 efficiently mounted an antigen-specific CD4 T-cell response and developed experimental autoimmune encephalomyelitis. We showed that immunization of VelociT mice with an HLA-A2 restricted cancer-derived peptide induced cytotoxic CD8 T cells capable of lysing peptide-pulsed target cells in an antigen-specific manner. Finally, we successfully established an allogeneic skin graft mouse model by showing that VelociT recipient mice rejected Balb/c donor skin grafts. This work established VelociT mice as a platform for investigation of T cell–mediated immunity in different disease settings including autoimmunity, antitumor responses, and allo-immunity.
Unexpected expression and function of Fc epsilon RI in breast cancer cells.
Authors: Pullen Nicholas , Ashbaugh Alexandria , Haughian James 
Published: November 2024

Abstract
FcεRI is typically associated with type 2 effectors such as mast cells (MC). The unique expression profile of FcεRI and evidence from pre-clinical and clinical settings have led us to study MC as potential therapeutic targets in breast cancer. Our work with the 4T1 model in vivo identified MC interacting with tumor cells, but this was complicated by a surprising finding that tumor cells intrinsically expressed FcεRI. Here we further study the expression and function of FcεRI in breast cancer cells in vitro. 4T1 cells express FcεRI similar to mouse BMMC. Two established cultures derived from human T-47D cells, estrogen dependent (E3) and estrogen withdrawn (EWD8), also express FcεRI: EWD8 cells are strong FcεRI expressers while E3 are modest, compared to LAD2 cells, a human MC line. Expression (mRNA) of all FcεRI subunits (α, β, γ) was confirmed. IgE-mediated antigen stimulation does not elicit classic Ca2+ flux in breast cancer cells as seen in respective species MC; however, it can stimulate IL-6 production from them. Preliminary analysis of primary breast cancer datasets using R2 is ongoing and discordant with our in vitro work: FcεRI mRNA abundance declines in metastatic cancers compared to non-cancerous breast tissue. We report a previously unidentified, immunologically substantive difference between breast cancer models and human primary tumors. Investigators pursuing FcεRI-relevant therapeutics in this context should be aware of this potential translational barrier.
ST8Sia6 sialylates CD44 in cancer cells to generate ligands for inhibitory Siglecs
Authors: Chen Yin Maggie , Friedman David , Saraswat Mayank , Chen Alex Shuaibo , Shapiro Michael , Wilfahrt Drew , Pandey Akhilesh , Smith Shapiro Virginia 
Published: November 2024

Abstract
Glycans decorate most proteins and lipids on the cell surface, and glycoproteins serve a critical role in cell-cell communication. The terminal modification of many glycans is a sialic acid. There are twenty mammalian sialyltransferases, each with a unique specificity. Recently, we demonstrated that the sialyltransferase ST8Sia6, which adds an alpha-2,8 linked sialic acid, generates ligands for the inhibitory receptor Siglec-E. ST8Sia6 overexpression accelerates tumor growth though inhibition of the immune response through Siglec-E. To understand the basis for ST8Sia6 function in tumors, proteomic analysis of murine tumor lines was performed to identify ST8Sia6 targets. Here, we demonstrate that ST8Sia6 sialylates CD44. Siglecs vary significantly across species, with the closest ortholog to murine Siglec-E is Siglec-7 in humans. We also show that ST8Sia6 sialylates CD44, generating ligands for Siglec-7. Thus, ST8Sia6 has a conserved role in both mice and humans to generate ligands for Siglecs. We also found that sialyltransferase ST6GalNac1 which adds an alpha-2,6 sialic acid to CD44, generating ligands for Siglec-7. The TCGA database showed synergistic effect of CD44 and ST8Sia6 decrease patient survival, while CD44 and ST6GalNac1 increases patient survival. Thus, CD44 is a target for ST8Sia6 and ST6GalNac1that generate ligand for inhibitory Siglecs, but the immunomodulatory effect may differ between two types of modifications, which is under current investigation.
Determining the Effects of Obesity and Type 2 Diabetes on CCR6+ Epidermal GD T Cell Number and Function in Inflammatory Disease and Wound Healing
Authors: Engel Emma , Alvizo Cristian , Castellanos Tanya , Bshara-Corson Savannah , Kasler Antolette , Lawler William , Jameson Julie 
Published: November 2024

Abstract
A maladaptive healing cascade causes chronic wounds. γδ T cells are affected, the dysregulation of which causes a reduction of cytokines and growth hormones. We are studying the Chemokine Receptor 6 (CCR6)/Chemokine Ligand 20 (CCL20) axis and how it functions in the wounds of obese and diabetic mice. When keratinocytes are stressed by wounding or psoriasis, CCL20 is released and interacts with CCR6 on Dermal T cells to recruit them to the epidermis. Epidermal T cells and their role in this axis are not as well understood. Upon wounding, it was found that a subset of epidermal γδ T cells express CCR6 within 24 hours, and it is downregulated by 72 hours. The role of the CCR6 epidermal γδ T cells express was also investigated. Epidermal γδ T cells, when co stimulated with CCL20 and anti-CD3, generate IL-17A, suggesting that CCR6 plays a role in TH17 responses during inflammation. Animals and humans with obesity and diabetes both exhibit elevated IL-17, so obese and diabetic mice were examined during wound healing and psoriasis.
During keratinocyte stress, epidermal gd T cells experienced significantly elevated levels of CCR6 and IL-17 in obese and diabetic mice. This shows that in chronic diseases like type 2 diabetes, resident T cell IL-17 responses are amplified. In better understanding the mechanisms used by resident T cells during their inflammatory responses to keratinocyte stress, a targeted therapy can be developed to help treat chronic wounds and psoriasis.