bluuebunny/crossref_metadata_2025_split huggingface dataset:
The lack of NK and mCD8+ T cells in IL-15KO mice confers resistance to septic shock
Authors: Guo Yin , Luan Liming , Bohannon Julia , Patil Naeem , Fensterheim Benjamin , Hernandez Antonio , Wang Jingbin , Sherwood Edward 
Published: January 2023

Abstract
Septic shock remains one of the leading causes of death in the USA. However, the immunological mechanisms of septic shock are still not well understood. Interleukin (IL)-15 is an essential mediator for natural killer (NK) and memory (m) CD8+T cell survival, as indicated by the deficits of these cells in IL-15 knockout (KO) mice. As NK and CD8+T cells are implicated in the pathogenesis of septic shock, we hypothesized that IL-15KO mice will be resistant to septic shock due to their lack of NK and mCD8+T cells. IL-15KO mice showed a significant survival advantage over wild type (WT) control mice during septic shock caused by cecal ligation and puncture (CLP) or LPS challenge. IL-15KO mice displayed less sepsis-induced hypothermia and attenuated plasma IL-6 production in our sepsis models. Treatment with low-dose IL-15 superagonist (SA) regenerated NK and mCD8+T cells in IL-15KO mice and reestablished mortality in these mice during CLP- and LPS-induced septic shock. However, if NK and CD8+T cell regeneration was prevented by anti-asialoGM1 and anti-CD8α prior to IL-15 SA treatment, IL-15 SA failed to reestablish sepsis-induced mortality in IL-15 KO mice. When given to WT mice 4 days prior to CLP or LPS challenge, M96, an IL-15 neutralizing IgG, caused 80.8% depletion of splenic NK cells and conferred protection against septic shock. However, when given shortly prior to CLP or LPS challenge, M96 did not deplete splenic NK cells and failed to confer protection against septic shock. In conclusion, IL-15 contributes to the lethality of septic mice by maintaining NK and mCD8+ T cell populations, but does not play a direct role in septic shock. Thus, NK and mCD8+ T cells may represent effective therapeutic targets for septic shock.
Identifying key regulators of CD4 T cell function in the Mycobacterium tuberculosis-infected lung using systems analysis
Authors: Delahaye Jared L , Cohen Sara , Plumlee Courtney , Plaisier Christopher , Baliga Nitin , Urdahl Kevin 
Published: January 2023

Abstract
Mycobacterium tuberculosis (Mtb) infection is the leading infectious killer worldwide and an effective vaccine remains elusive. Although CD4 T cells are known to be important for protection, the specific requirements for a protective CD4 response are unclear. Our lab has shown that differences in antigen exposure drive significant phenotypic variation within Mtb-specific CD4 T cells. CD4 T cells specific for the Mtb protein Ag85B, which is only expressed early during infection, remain capable of robust cytokine production. Conversely, T cells specific for ESAT-6, which is expressed for the duration of infection, exhibit blunted cytokine production. To identify regulators that govern this T cell exhaustion, we employed a systems biology approach. We performed RNA-seq on unstimulated and stimulated Ag85B and ESAT-6-specific CD4 T cells isolated from the lungs of Mtb-infected mice and used cMonkey, a biclustering algorithm, to create gene clusters based on expression patterns and identify transcription factors predicted to regulate the clusters. This analysis revealed eight transcription factors that were themselves differentially expressed between Ag85B and ESAT-6-specific CD4 T cells and also predicted to regulate clusters of differentially expressed genes. We are currently focusing our analysis on two of these transcription factors, VDR and Lyl-1. Mtb infection of WT:VDR−/− mixed bone marrow chimeras have validated the systems-based predictions by showing that VDR regulates distinct processes in Ag85B-specific compared to ESAT-6-specific CD4 T cells. Understanding the disparate regulatory pathways operant in functional vs. exhausted T cells may inform new avenues for host-directed therapy of tuberculosis.
Age-associated defects impair the optimal development of a protective immune response to Clostridium difficile in the context of infection in a novel aged murine model
Authors: Bernui Mariana Estrella , Kutzler Michele A. 
Published: January 2023

Abstract
Clostridium difficile infections (CDI) is a major source of mortality in the US, especially among the elderly. Protection against CDI is mediated by anti-toxin host antibodies (Ab). Although it is known that elderly mount an impaired anti-toxin response, it is yet to be determined whether their lower Ab levels are due to defective germinal center (GC) priming during acute CDI that leads to defective B cell proliferation and maturation. To test our hypothesis, we developed an antibiotic mucosal spore challenge CDI model and infected young (4mo.) and aged (&gt;18mo.) mice with UK1 hypervirulent C. diff spores. By day 4 post-infection 100% of the aged had succumbed to infection compared to only 10% of young mice. Following a sublethal spore challenge a significant decrease of total PD1+CXCR5+ Tfh cells was detected in aged compared to young at Day 12 and 21 PI (p&lt; 0.05 and p&lt; 0.03, respectively). We also observed a marked decline of total and antigen-specific CD19+PNA+CXCR5+ B cells in our aged cohort (p&lt; 0.05). We re-challenged with a lethal dose 1 month later. Only 50% of the aged vs 100% of the young survived. At Day 7 post re-challenge (D37) there was a decrease in total GC B cells (M= 7.2% SD+/−1.8 in aged vs M=15.8% SD+/−3.3 in young) and no change in Tfh cells (M= 7.5% SD+/−0.7 in old vs M=8.2% SD+/−2.1 in young). Further, the frequency of anti-toxin-specific B cells was significantly decreased in the aged (p= 0.02). The frequency of toxin-specific IgG, IgM and IgA ASC, and serum and mucosal toxin-specific Ab were markedly reduced in the aged. Our data suggests aged mice are more susceptible to CDI due to a defect in early GC formation, leading to an impaired antigen-specific Ab response. Overcoming this could prevent age-associated recurrence and severe CDI.
Cardiac dysfunction during Francisella novicida bacterial infection; an instructive sepsis model to study heart function
Authors: Rajaram Murugesan , Makara Michael , Hoang Ky , Ganesan Latha Prabha , Crouser Elliott , Gunn John , Turner Joanne , Schlesinger Larry S , Mohler Peter 
Published: January 2023

Abstract
Francisella novicida (Ft.n) is a gram negative intracellular pathogen that causes severe sepsis syndrome. Sepsis patients with cardiac dysfunction have significantly higher mortality. Although several pathways have been associated with myocardial damage in sepsis, the precise cause(s) remains unclear and treatment options are limited. We have shown that Ft.n infection causes rapid dissemination, inflammation and sepsis in the mouse model, however, the basis for cardiac dysfunction during Ft.n infection is unknown. In our Ft.n sepsis model we have observed ECG abnormalities such as R’ wave formation, prolonged QRS and PR intervals, left ventricular wall thickening and increased cardiac output, similar to sepsis patients. Notably, we detected microlesions in the myocardium, and also seen in nosocomial Streptococcus infection and in sepsis patients. We have also determined that Ft.n-mediated microlesions are due to cardiomyocyte apoptosis due to increased infiltration of leukocytes and expression of inflammatory mediators (TNFα, IL-1β, IL-8 and SOD2). Finally we have found increased expression of miR155 and rapid degradation of HSF-1 in the heart suggesting that these processes regulate myocaridal inflammation and apoptosis. In conclusion, we have developed and used an Ft.n infection model to study the pathogenesis of heart dysfunction during sepsis.
Reduced lung-resident T cell memory in infants following influenza infection
Authors: Zens Kyra D , Farber Donna L 
Published: January 2023

Abstract
Influenza is a major cause of morbidity and mortality in infants, who suffer more severe disease and are more susceptible to reinfection. In adults, influenza generates robust lung tissue-resident T cell memory (TRM) populations which are protective upon subsequent infection. Using a mouse model, we investigated whether infants also establish lung TRM after influenza infection. We found that infants and adults mount similar primary lung T cell responses to influenza. However, following recovery, infected infants generated fewer lung TRM than did animals infected as adults. Mice infected as infants also suffered greater weight loss and increased lung viral titers upon reinfection as adults in a TRM-dependent manner. Reciprocal transfer of infant or adult antigen-specific CD4 T cells to adult or infant hosts revealed that while both infant and adult cells expand in the primary response, only adult cells are efficiently maintained as TRM after resolution of infection suggesting a cell-intrinsic cause for reduced TRM in infants. RNAseq analysis of infant and adult primary effectors revealed increased T-bet and strongly decreased levels of Eomes and the survival factor Bcl-2 in infant T cells while analysis of protected lung memory from animals infected as infants or adults demonstrated lower levels of TRM-associated retention markers and decreased levels of the survival factors Bcl-2 and Bcl-xL. Further pathway analysis implicated reduced IL-7 and IL-15 signaling in infant T cells suggesting a mechanism for their reduced TRM with important implications in vaccine design and therapies for influenza in this population.
IL-15 supports the generation of lung tissue-resident memory CD4 T cells
Authors: McKinstry Karl Kai , Finn Caroline , Swain Susan L 
Published: January 2023

Abstract
Increasing evidence from animal models and human studies points towards a critical role for tissue-resident memory T cells (TRM) during protective recall responses. TRM able to persist at sites of infection may be especially important for clearance of pathogens such as influenza A virus (IAV) that can evade neutralizing antibody. We recently showed that while virtually all memory CD4 T cells that develop in secondary lymphoid organs following IAV priming require autocrine IL-2 signals, a population of CD69high CD127low lung CD4 TRM is generated through a unique IL-2-independent pathway. Here, using several different experimental approaches, we find that formation of this TRM subset is dependent on IL-15 signals received during the first week of IAV infection. Long-term maintenance of the TRM cells, however, does not require IL-15 or the recognition of residual IAV antigen. Finally, our results demonstrate that IL-15-dependent TRM cells can more efficiently elicit pro-inflammatory responses from dendritic cells presenting cognate peptide antigen than can conventional splenic memory CD4 T cells expressing the same T cell receptor, a function that correlates with initial control of viral titers during the first few days following IAV challenge. These studies, identifying a novel role for IL-15 in supporting the generation of a subset of lung CD4 TRM cells with specialized function following IAV priming, are highly relevant to vaccine design.
Pyruvate kinase type M2 promotes tumor cell exocytosis via phosphorylating synaptosome-associated protein-23
Authors: Liu Yuan , Wei Yao , Pan Chaoyun , Zhu Dihan , Shi Lei , Bian Zhen , Zen Ke 
Published: January 2023

Abstract
Tumor cells secret large amount of microvesicles (MVs) which are involved in remodeling tumor-stromal interactions to promote malignancy. The regulatory mechanisms governing the active exocytosis in tumor cells, however, remain incompletely understood. We show here that tumor cell exocytosis is tightly controlled by aerobic glycolysis (Warburg effect) and pyruvate kinase type M2 (PKM2), which is commonly upregulated and phosphorylated in tumor cells, plays critical roles in promoting exocytosis. Upon stimulation by EGF, more phosphorylated PKM2 switches to dimer form and is recruited to exosomes where it associates with synaptosome-associated protein (SNAP)-23 (SNAP-23). The association of PKM2 and SNAP-23 in secreted exosomes is confirmed by cross immunoprecipitation and Western blot analysis. Dimerized PKM2 enhances the exosome release via phosphorylating SNAP-23. Direct phosphorylation assay and mass spectrometry identifies SNAP-23 phosphorylation at Ser95by PKM2. Ectopic expression of non-phosphorylated SNAP-23 mutant (Ser95→Ala95) significantly reduces PKM2-mediated exocytosis whereas phosphomimetic SNAP-23 mutants (Ser95→Ele95) partially rescue the impaired exocytosis in tumor cells with PKM2 knockdown. Our findings reveal a previously unrecognized non-metabolic function of PKM2 in promoting tumor cell exocytosis.
PDL1 expression is elevated prior to AIDS-related Non-Hodgkin’s lymphoma diagnosis
Authors: Epeldegui Marta , Conti David , Guo Yu , Cozen Wendy , Penichet Manuel , Martinez-Maza Otoniel 
Published: January 2023

Abstract
The risk of developing non-Hodgkin’s lymphoma (NHL) is greatly elevated in HIV infection, and AIDS-associated NHL (AIDS-NHL) remains a significant problem, even in those receiving anti-retroviral therapy. AIDS-NHL is thought to develop due to: 1) loss of immunoregulation of Epstein-Barr virus infected cells and/or 2) the accrual of genetic errors associated with B-cell activation driven by HIV infection. A population of B cells that express PDL1, secrete CXCL13, IL6 and IL10, and can regulate T-cell function by interacting with PD1, has been recently described. We previously showed that serum levels of CXCL13, IL-16 and IL-10 are elevated prior to, as well as after, AIDS-NHL diagnosis. Also, others have described that PDL1 and PD1 expression are elevated in HIV infection, and that this has an impact on T-cell function. PDL1 expression on B cells may contribute to the development of AIDS-NHL in a dual fashion by: 1) enhancing B-cell activation, and 2) by impairing/inhibiting T-cell function through PD1:PDL1 interactions. Hence, we hypothesized that levels of CD19+PDL1+ cells may be elevated prior to AIDS-NHL diagnosis and may play a role in lymphomagenesis. To investigate this hypothesis, we conducted a nested case-control study within the Multicenter AIDS Cohort Study, obtaining viable frozen PBMC from HIV+ subjects who later developed NHL (cases, n=31) and from HIV+ subjects who did not develop NHL (HIV+ matched controls, n=29) and performed multi-color flow cytometry. We observed that the numbers of circulating CD19+PDL1+ cells in cases were elevated prior to AIDS-NHL diagnosis, when compared to HIV+ controls (p=0.026), suggesting that CD19+PDL1+ cells may be playing an important role in the development of AIDS-NHL.
Thymic stromal lymphopoietin promotes interplay between breast tumor cells, neutrophils and Ly6Chi monocytes to regulate breast tumor progression
Authors: Kuan Emma Lo , Ziegler Steven F 
Published: January 2023

Abstract
Various human cancers display a T helper type 2 (Th2)-like inflammation. One possible mechanism suggested in human breast cancers is thymic stromal lymphopoietin (TSLP) secreted by breast tumor cells which can drive Th2 responses via tumor-associated dendritic cells. However, the interactions between TSLP, tumor cells, and other immune cells remain unclear.
We found in breast tumor-bearing mice TSLP can also be produced by two pro-tumor myeloid cell populations, neutrophils and Ly6Chi monocytes. This non-tumor derived TSLP is crucial for both primary breast tumor growth and its metastasis to lungs. One important mechanism is myeloid derived TSLP can directly act on tumor cells and promote survival and TSLP production of tumor cells. Mice transplanted with TSLPR deficient breast tumor cells developed smaller primary breast tumors and fewer lung metastases. Conversely, mice that constitutively express TSLP in lungs transplanted with breast tumor cells had markedly increased lung metastases. Blocking TSLP in lungs resulted in a reduction in the number of lung metastases. We further discovered that TSLP signaling in Ly6Chi monocytes is crucial for their suppressor functions and their ability to differentiate into macrophages in tumors. Transfer of TSLP receptor deficient Ly6Chi monocytes significantly reduced lung metastases in tumor-bearing mice by changing T cell populations in lungs and in tumors.
Our work is the first to show myeloid cell derived TSLP plays an important role in promoting breast tumor progression via maintaining tumor cell survival. We also provide a novel mechanism of the requirement of TSLP signaling in differentiation and suppressor functions in Ly6Chi monocytes.
Adrenergic signaling mediates immune suppression induced by cool housing temperatures for laboratory mice
Authors: Bucsek Mark J , Qiao Guanxi , Liu Haichao , Evans Lauren , MacDonald Cameron , Hylander Bonnie , Repasky Elizabeth A 
Published: January 2023

Abstract
Our laboratory has demonstrated that standard mildly cool housing temperatures (ST, 22°C) can significantly enhance tumor growth by suppressing anti-tumor immunity. In contrast, we have found that maintaining mice at thermoneutral temperatures (TT, 30°C) reversed immunosuppression and significantly delayed tumor growth compared to ST. Under cool conditions, mammals produce heat via adaptive thermogenesis, a process which is driven by norepinephrine (NE) acting through β-adrenergic receptors (β-ARs) on brown adipose cells and we found that NE is significantly elevated in mice at ST compared to TT. NE is known to suppress immune cell activity. We therefore hypothesized that cool housing conditions elevate NE which then suppresses anti-tumor immunity. To investigate this hypothesis, we used two syngeneic mouse tumor models: 4T1 mammary carcinoma and B16-OVA melanoma. In tumor bearing mice at ST, the β-AR antagonist propranolol significantly delayed tumor growth. β-blockade had no effect on the growth of 4T1 tumors in immunodeficient SCID mice indicating a mechanism involving the adaptive immune response. In mice bearing B16-OVA tumors, β-blockade also slowed tumor growth and this beneficial effect was negated by CD8+ T-cell depletion. In both models, reversing adrenergic stress induced immunosuppression by β-AR blockade in combination with boosting the anti-tumor T cell response by blocking programmed cell death receptor 1 (PD-1) significantly slowed tumor growth in mice housed at ST compared to either treatment alone. Therefore, combination therapy with β-receptor antagonists could improve the clinical efficacy of immunotherapy, including checkpoint inhibition.
CXCR4 is required for progression of T cell acute lymphoblastic leukemia
Authors: Chen Cynthia , Pitt Lauren , Tikhonova Anastasia , Aifantis Iannis , Schwab Susan Ruth 
Published: January 2023

Abstract
Of the most common childhood cancer, acute lymphoblastic leukemia (ALL), 15% of cases are caused by transformation of T cell progenitors (T-ALL). While survival rates have vastly improved for newly diagnosed T-ALL, substantial challenges remain in the treatment of relapsed disease and in the minimization of side-effects from central nervous system prophylaxis. Hence, the search for more effective, less toxic treatments continues. Homing receptors play multiple roles in cancer progression, yet little is known about the trafficking of T-ALL. Upon profiling homing receptor expression, we found high levels of the chemokine receptor CXCR4 on the surface of mouse and primary human T-ALL cells. Furthermore, T-ALL cells localized in close proximity to CXCL12-producing stromal cells in mouse femoral bone marrow. Deletion of Cxcl12 in vascular endothelial cells limited leukemia progression, suggesting a vascular niche for T-ALL. In parallel, we found CXCR4 expression to be essential for T-ALL maintenance and progression. Deletion of Cxcr4 in mouse T-ALL after disease onset led to disease remission and prolonged survival, and CXCR4 antagonism using the small molecule inhibitor AMD3465 suppressed human disease in a patient-derived xenograft model. Loss of CXCR4 signaling in T-ALL cells reduced Myc abundance, which was previously reported to regulate leukemia-initiating cell activity. In line with this, CXCR4-deficient T-ALL cells failed to establish disease when adoptively transferred into secondary hosts. Together, our findings highlight an important contribution of microenvironment in regulating T-ALL pathogenesis, and suggest targeting CXCL12:CXCR4 signaling as a powerful new strategy for treating this aggressive disease.
Low Dose Gemcitabine plus TH1 Dendritic Cell Vaccination Mediates Durable Cure of Orthotopic KrasG12D/p53−/− Pancreatic Ductal Adenocarcinoma via the Generation of Atypical CD3+CD8+NK1.1+ T-cells
Authors: Konduri Vanaja , Li Dali , Halpert Matthew M. , Liang Dan , Liang Zhengdong , Chen Yunyu , Fisher William E , Levitt Jonathan M , Yao Qizhi Cathy , Decker William K 
Published: January 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in the United States with a five-year overall survival of only 7%. To explore the potential of immune-based treatment approaches to PDAC, we treated orthotopically-established K-rasG12D/p53−/− PDAC tumors with 40 mg/kg gemcitabine and a cell-based therapeutic vaccine previously shown to generate robust and durable cell-mediated (TH1) immunity. The results indicated that the combination of chemotherapy and a TH1 dendritic cell (DC) vaccine was effective in eliminating tumor, preventing metastasis and recurrence, and significantly enhancing OS. No animal that received the combination therapy relapsed, while 80% of mice that received gemcitabine-only relapsed and progressed. Analysis of circulating PBMC demonstrated that mice receiving the combination therapy exhibited significantly elevated levels of IFN-γ+CCR7+CD8+ T-cells with significantly reduced levels of exhausted GITR+CD8+ T-cells after the cessation of treatment. Retro-orbital tumor re-challenge of surviving animals at six months after treatment demonstrated durable antitumor immunity only among mice that had received the combination therapy. CD8+ splenocytes derived from surviving mice that had received the combination therapy were sorted into NK1.1pos and NK1.1neg populations and adoptively transferred into naïve recipients. Transfer of only 1,500 CD8+NK1.1pos T-cells was sufficient to mediate tumor rejection whereas transfer of 1,500 CD8+NK1.1neg T-cells imparted only minimal effects. The data suggest that addition of a TH1 DC vaccine regimen as an adjuvant to existing therapies can mediate eradication of tumors and offer durable protection against PDAC.