bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inflammasome-associated inflammation inhibits cell-mediated immune responses to Listeria monocytogenes
Authors: Theisen Erin M , Sauer John-Demian 
Published: January 2023

Abstract
Listeria monocytogenes is a genetically tractable Gram-positive intracellular bacterium that activates a robust cell-mediated immune response capable of breaking self-tolerance. These properties contribute to its success as a cancer immunotherapeutic platform; however, despite these attributes, the specific mechanisms by which L. monocytogenes stimulates a robust adaptive immune response remain largely unknown. We hypothesized that cytosolic innate immune activation, specifically inflammasome activation, by L. monocytogenes would be critical for triggering a robust CD8+ T-cell response. Surprisingly, we found that inflammasome activation impairs the induction of antigen specific T-cells and ultimately the generation of protective immunity. To determine if this phenomenon is unique to inflammasome-induced pyroptosis or a general outcome of pathogen induced host cell death, we designed strains of L. monocytogenes to uniquely activate pyroptosis, necrosis, or apoptosis.
Contrary to previous studies of immunity in the context of sterile cell death, pathogen induced pyroptosis, necrosis and apoptosis each impaired the generation of cell-mediated immunity. Importantly, the mechanism of impairment was unique for each form of cell death, although in each case it was independent of dendritic cell depletion or deficits in antigen presentation. Apoptosis and necrosis impaired dendritic cell co-stimulatory molecule expression, while the pyroptotic inflammatory milieu independently impaired the generation of cell-mediated immunity. These results suggest that inhibition of inflammasome activation, or specifically certain inflammatory components, is critical for the success of L. monocytogenes immunotherapy.
Understanding heterogeneous CTL responses to the yellow fever vaccine using mathematical models.
Authors: Moore James R , Antia Rustom , Akondy Rama , Jia Jonathan , Ahmed Rafi 
Published: January 2023

Abstract
In an acute infection, such as those caused by attenuated vaccines, we should expect the immune response to depend in some manner upon the precursor frequency as well as the magnitude of the viral load within the patient. However, we do not have a quantitative understanding of this process. In a recent study, 80 patients received the yellow fever vaccine and their viral titer and T-cell responses were tracked for several days. It was found that there were substantial differences between individuals in peak viral load, but that the difference in CTL response was relatively small. Moreover, although the CTL response was positively correlated with viral load, the response saturated for high viral loads. Using mathematical models, we investigated which rules of T-cell proliferation could give rise to this pattern. We considered three models: antigen-dependent proliferation in which the T-cells must receive continuous antigen stimulation to continue to divide, programmed proliferation in which T-cells commit to a fixed number of division upon recruitment and a hybrid model in which T-cells commit to a variable number of division based on viral load. We find that this latter model is the most plausible description of the data. We also considered whether negative feedback in the form of T-cell competition may play a role in determining CTL response, however we found no evidence for any such mechanism.
Coincident Type 2 diabetes mellitus modulates the systemic and antigen – specific induction of Type 1, Type 17, and other cytokines in both active and latent tuberculosis
Authors: Babu Subash , Kumar Nathella Pavan , Nutman Thomas B 
Published: January 2023

Abstract
Type 2 diabetes mellitus (DM) is known to be a major risk factor for the development of active tuberculosis, although its influence on active and latent Mycobacterium tuberculosis infection and disease remains poorly characterized. To identify the influence of coincident DM on cytokine levels in active pulmonary tuberculosis and latent tuberculosis, we examined circulating levels of a panel of cytokines in the plasma of individuals with PTB-DM or PTB alone and LTB-DM or LTB alone. PTB-DM is characterized by elevated circulating levels of type 1 (IFNγ, TNFα, and IL-2), type 2 (IL-5), type 17 (IL-17A) but decreased circulating levels of IL-10 family of cytokines (IL-19, IL-20, IL-22 and IL-24). This was associated with increased systemic levels of other pro-inflammatory cytokines (IL-1β, IL-6, and IL-18) and an anti-inflammatory cytokine (IL-10) but not type 1 IFNs. In contrast, LTB-DM is characterized by diminished circulating levels of type 1 (IFNγ, IL-2, and TNFα), type 17 (IL-17F), IL-10 family (IL-10, IL-19, IL-20 and IL-24) and other pro-inflammatory (IL-1β and IL-18) cytokines. Moreover, PTB-DM showed increased levels of pro-inflammatory cytokines upon tuberculosis antigen stimulation whereas LTB-DM showed diminished pro-inflammatory cytokines upon tuberculosis antigen stimulation. Our data reveal that PTB-DM is characterized by heightened cytokine responsiveness, indicating that chronic inflammation underlying DM potentially contributes to increased immune pathology. On the other hand, LTB-DM is characterized by diminished production of cytokines, implicated in the control of M. tuberculosis, allowing for a potential immunological mechanism that could account for the increased risk of active tuberculosis.
The immunogenic HSP receptor CD91 is an essential mediator of tumor immunosurveillance
Authors: Sedlacek Abigail L , Zhou Yu Jerry , Binder Robert J 
Published: January 2023

Abstract
Immunogenic Heat Shock Proteins (HSPs) are capable of eliciting potent immune responses against their chaperoned antigens and are being investigated as a potential cancer immunotherapy. HSPs signal through the receptor CD91 on the surface of antigen presenting cells and result in the development of a Th1 immune response. We have previously shown that when antigen load is low, HSPs and CD91 are required to prophylactically immunize against tumor development. Since antigen load is also low during nascent tumor development, we hypothesized that CD91 is critical during tumor immunosurveillance. We induced tumors using methylcholanthrene in CD91fl/flx CD11cCremice as well as CD91fl/fllittermates. Tumors developed more rapidly and at a higher incidence in the CD91fl/flx CD11cCremice as compared to the littermate controls. Additionally, tumors in these animals grew more progressively. We are currently immune-phenotyping the tumors that develop in each cohort at multiple time points to determine how the lack of CD91 on CD11c+ cells influences the immune cell infiltrate. Collectively, our data demonstrate that CD91 is a critical mediator of tumor immuneosurveillance and influences the immune infiltration of developing tumors.
Autoreactive CD8+ T-cells are highly dependent on CD8 for activation and as such targeting CD8 is an effective way of blocking autoreactive CD8+ T-cell activation
Authors: Wooldridge Linda , Morgan David , Pearson James Alexander , Gras Stephanie , van den Berg Hugo , Lissina Anya , Llewellyn-Lacey Sian , Willis Mark , Dockree Tamsin , McLaren James E , Ekeruche-Makinde Julia , Gostick Emma , Robertson Neil , Rossjohn Jamie , Burrows Scott R , Price David , Wong Susan , Peakman Mark , Skowera Ania , Clement Matthew 
Published: January 2023

Abstract
Autoimmune diseases such as type I diabetes (TID) and multiple sclerosis (MS) are chronic conditions that have a significant impact on quality of life. CD8+ T-cells play an important role in the pathogenesis of these diseases. However, drugs that target the entire CD8+ T-cell population are not desirable because this population provides protection against infection. Accordingly, there is an urgent requirement to develop novel treatment strategies that exclusively target the autoreactive CD8+ T-cell population. CD8+ T-cells express a molecule called CD8 at their cell surface which assists with activation. We have demonstrated that autoreactive CD8+ T-cells are entirely dependent on CD8 for activation. In stark contrast, pathogen specific CD8+ T-cells are characterized by higher functional sensitivity and are relatively CD8 independent. This represents an intrinsic difference that can be exploited for therapeutic benefit. Our data suggests that “blocking anti-CD8 antibodies” can be used to block autoreactive CD8+ T-cell attack without affecting pathogen specific immunity, a key goal in the treatment of autoimmunity. The generation of “blocking anti-CD8 antibodies” offers an opportunity to develop a novel therapeutic approach that can be used to treat CD8+ T-cell mediated autoimmunity. In order to conduct a further assessment, we are currently developing a strategy for in vivo validation of the approach.
Ras-mediated missing-self recognition via NKR-P1B:Clr-b interactions facilitates detection of oncogenic transformation and cancer immunosurveillance
Authors: Tanaka Miho , Fine Jason H. , Kirkham Christina L. , Aguilar Oscar A. , Ketela Troy , Moffat Jason , Allan David S.J. , Carlyle James R. 
Published: January 2023

Abstract
Natural killer (NK) cells are involved in tumor immune surveillance, immunity to infection, and various pathological conditions. One mode of NK cell recognition, ‘missing-self’ recognition, is triggered by downregulation of inhibitory self ligands on target cells, thereby decreasing the net signaling threshold to promote NK cell activation. Clr-b, ligand for the NKR-P1B inhibitory NK receptor, is downregulated during cellular transformation, viral infection, and genotoxic stress, in turn promoting MHC-independent missing-self recognition. However, the mechanisms underlying the loss of Clr-b during oncogenic transformation remain unknown. Here, we demonstrate that proto-oncogene, Ras, is directly involved in Clr-b downregulation on mouse fibroblasts via the Raf/MEK/ERK and PI3K pathways. We show that c-myc overexpression also promotes Clr-b downregulation. To examine a link between the loss of Clr-b and tumour progression using a spontaneous B cell lymphoma model, we backcrossed the Emu-c-myc transgene onto a Clr-b−/− background, then assessed the survival rates of transgenic littermates. Preliminary results reveal a trend towards accelerated tumor progression of Clr-b+/+ littermates versus Clr-b+/− littermates, suggesting a potential protective role for Clr-b loss in tumour immune surveillance, one revealed under loss-of-heterozygosity conditions. Notably, previous results using Nkrp1b−/− mice also suggest that NKR-P1B-mediated inhibition may also facilitate deleterious tumour immune escape. Collectively, our data suggest that Clr-b downregulation during oncogenic transformation plays a role in the detection of oncogenic transformation and cancer immunosurveillance by NK cells.
Natural Killer cells from primary human head and neck squamous cell carcinomas upregulate NKG2A
Authors: Korrer Michael J , Kim Young 
Published: January 2023

Abstract
Immunotherapy has revolutionized cancer therapy primarily by targeting checkpoint inhibitors found on endogenous immune cells. We analyzed and compared NK cells from the blood and tumor of HNSCC patients by flow cytometry for the expression of NK cell activating and inhibitory receptors. We found that NK cells from the primary tumor, but not the blood of HNSCC patients, significantly downregulated activating receptors NKG2D, DNAM-1, NKp30, CD16 and 2B4. Surprisingly, the majority of inhibitory KIR receptors on tumor-infiltrating NK cells were decreased compared to NK cells from the blood. However, the inhibitory receptors NKG2A and PD-1 were found to be highly overexpressed in tumor-associated NK cells. We believe that this study provides the first in-depth look at NK cells from primary HNSCC tumors. We found that tumor-associated NK cells express a profoundly different phenotype than NK cells from the blood of the same patients, with multiple activating receptors downregulated and the inhibitory receptor NKG2A over-expressed. These results support the therapeutic strategy of targeting NKG2A.
Toll-like receptors 2 and 4 are necessary to generate a fully functional commensal-specific ocular immune response.
Authors: Almaghrabi Fatimah , St Leger Anthony , Caspi Rachel R 
Published: January 2023

Abstract
Conjunctiva-associated lymphoid tissue (CALT) resembles a conventional mucosal immune tissue, which harbors various immune cells and is exposed to a wide array of microorganisms at the ocular surface. In a recent study, we demonstrated that colonization of the ocular mucosa with the commensal bacterium, Corynebacterium mastitidis (C. mast), results in increased resistance of the ocular surface to infectious fungal and bacterial pathogens. Further, we showed that this effect is dependent on IL-17 produced by gd T cells that respond to C. mast. In this study, we used mice deficient in the toll-like receptors, TLR2 and TLR4, to examine the role of these receptors in generating a gdT-17 immune response at the ocular surface. In vitro, we show that these receptors are necessary on dendritic cells (DCs) to effectively induce IL-17 production and proliferation of Vg4+ T cells. In vivo, we show that TLR2 KO mice and TLR4 KO mice fail to recruit Vg4+ T cells and neutrophils to the conjunctiva. These data suggest that both TLR2 and TLR4 are required to generate a fully functional mucosal IL-17 response in the conjunctiva and its draining lymph nodes. Our data highlight the importance of innate receptors in the generation of the ocular mucosal immune response and maintenance of gd T cell responses in vivo.
SMN deficiency alters the CNS and the peripheral immune system in a mouse model of spinal muscular atrophy (SMA)
Authors: Khairallah Marie-Therese , Franklin Craig , Simon Madeline , O’Day Siri 
Published: January 2023

Abstract
Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss or mutation of the SMN1 gene. SMA rises from the insufficient levels of the ubiquitously expressed survival motor neuron (SMN) protein and is characterized by progressive α-lower motor neuron (LMN) degeneration and muscle atrophy. SMN is vital to all tissues, and the specific vulnerability of the LMN is still puzzling. However, currently there is a growing list of tissues affected in SMA. Recently, we have analyzed the development and the immune components of SMA spleen and found a selective reduction of the red pulp (RD) and RP macrophages in SMA mice, while white pulp and lymphocyte populations were largely preserved. Furthermore, previous studies suggested a role of glia cells in LMN pathology. These findings prompt us to investigate the role of the immune system in SMA pathogenesis. Looking into the cytokines production in the widely used “SMNΔ7” mouse model of SMA, we found that at steady state there is a higher production of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in SMA central nervous system (CNS) that starts at an early symptomatic age and escalates at the late symptomatic time. However, the anti-inflammatory cytokine TGF-β had lower expression. Interestingly, after in vivo LPS stimulation, SMA astrocytes and splenocytes exhibit less potency in increasing the pro-inflammatory cytokines except for IL-1β that had significantly higher levels in SMA at all points. These findings suggest that there is a role of SMN in the homeostasis and function of resident macrophages in the CNS and the spleen, and denote a yet undiscovered immune component of SMA where targeting cytokines would be a potential new supportive therapy for SMA patients.
The inflamed phenotype in PD-L1 negative non-small cell lung cancer (NSCLC) and response to checkpoint inhibitors
Authors: Pabla Sarabjot , Dy Grace , Nesline Mary , Gandhi Shipra , Pandey Manu , Ernstoff Marc C. , Conroy Jeffrey M. , Glenn Sean , Burgher Blake , Andreas Jonathan , Giamo Vincent , Papanicolau-Sengos Antonios , Galluzzi Lorenzo , He Ji , Gardner Mark , Morrison Carl 
Published: January 2023

Abstract

Background
NSCLC with a PD-L1 tumor proportion score (TPS) by immunohistochemistry (IHC) of greater than 50% has a positive predictive value (PPV) of 42% for response to pembrolizumab. Across all tumor types and different checkpoint inhibitors (CPIs), the evidence supports the inflamed phenotype associated with responders. Currently very little is known about predicting response to CPIs in PD-L1 negative NSCLC. Additionally, the association of the PD-L1 negative NSCLC with the inflamed phenotype has not been well described.

Methods
PD-L1 (22C3) IHC and a custom NGS cancer immune gene expression assay were used to interrogate 50 NSCLC samples of which 23 were treated with one or more CPIs. PD-L1 TPS &gt;50% was considered positive for IHC. Select over expression of 43 genes related to T-cell activation and 11 genes associated with tumor infiltrating lymphocytes were considered positive for the inflamed phenotype. RECIST v1.1 was used to assess patient response.

Results
9 of the 50 samples were PD-L1 IHC positive and showed an inflamed phenotype. An additional 7 samples exhibited an inflamed phenotype that were PD-L1 IHC negative. Of the 23 patients that could be evaluated for response to CPIs, 9 showed an inflamed phenotype while 14 were non-inflamed.

Conclusion
A subset of PD-L1 IHC negative NSCLC patients with an inflamed phenotype show a favorable response rate to CPIs. No complete or partial responses were identified in patients that were PD-L1 IHC negative with a non-inflamed phenotype.
IFN-ɛ regulated innate immune responses in the female reproductive tract during Chlamydia infection
Authors: Horvat Jay C , Mayall Jemma R , Mangan Niamh E , Brown Alexandra C , Chevalier Anne , Starkey Malcolm R , Kim Richard Y , Hertzog Paul J , Hansbro Philip M 
Published: January 2023

Abstract
The immune processes involved in the clearance and immunopathology of Chlamydia infection in the female reproductive tract (FRT) are not well understood. In previous ground-breaking studies we showed that IFN-ɛ, a novel type I IFN that is exclusively and constitutively expressed in the FRT, plays an important role in protecting against Chlamydia infections. Here, we examined the effects of IFN-ɛ on innate immune processes in the FRT in order to elucidate the mechanisms by which IFN-ɛ protects against Chlamydia infections. Female WT and IFN-ɛ−/− C57BL/6 mice were pre-treated with progesterone and infected intra-vaginally with Chlamydia muridarum or sham-infected. Uterine horns were harvested and the effects of IFN-ɛ deficiency on immune factor expression and cellular infiltration were assessed using microarray/bioinformatics analyses, real-time qPCR and flow cytometry. IFN-ɛ uniquely regulated the expression of 744 genes at baseline and 802 genes during Chlamydia infection, and universally regulated the transcription of 61 genes, regardless of infection status. Of note, pathways associated with protective innate responses, such as IFN regulatory factor activation and pattern recognition receptor signalling were down-regulated in Chlamydia-infected IFN-ɛ−/− mice compared to WT controls. These changes correlate with a decrease in the expression of many important IFN-γ signalling molecules and number of IFN-γ-producing NK cells in the FRT during infection. These findings suggest that IFN-ɛ may protect against Chlamydia FRT infections by potentiating innate immune processes important for the clearance of infection, particularly pathways associated with IFN-γ signalling and the activation of NK cell responses.
Inhibition of Glycogen Synthase Kinase 3 beta Provides Adjuvant-like Effect on Antigen-specific CAR-T cells
Authors: Sengupta Sadhak , Sengupta Sudarshana , Sampath Prakash 
Published: January 2023

Abstract
Although strong CAR T cell mediated immune response in hematological tumors has been credited for its success in cancer remission, unfortunately the same cannot be replicated in solid tumors. Weak exposure to antigens in solid tumors results in less than optimal CAR T cell activation. This leads to anemic expansion of activated CAR T cells and early clonal contraction, which ultimately fails to induce a proper anti-tumor immune response. Addition of CD28 and other costimulatory signaling moieties, along with the use of supplementary IL2 therapy has been shown to be not sufficient to overcome this impediment and have its own cytotoxic limitations. Glycogen-synthase kinase 3 beta (GSK3β), a constitutively active signaling molecule in naïve T cells, is transiently inactivated during TCR-mediated T cell activation and has been attributed to rapid T cell proliferation. Pharmacological inhibition of GSK3β promotes antigen-specific CAR T cell proliferation that is supported by both increases in cell division as well as long-term survival of these T cells. GSK3β inhibition further promotes development of very specific CD8+ effector CAR T memory phenotype that can be modulated with variability in antigen exposure. Tumor-rechallenge experiments with these GSK3β-inhibited antigen- experienced CAR T cells resulted in 100% tumor elimination and progress-free survival in experimental animals. We predict that this adjuvant-like effect of GSK3β inhibition on activated CAR T cells will be the portent to successful implementation of CAR T immunotherapy against solid tumors.
IL-11 induces encephalitogenic Th17 cells
Authors: Kiapour Nazanin , Zhang Xin , Khan Tabish Hasan , Thamilarasan Madhan , Kapoor Sahil , Markovic-Plese Silva 
Published: January 2023

Abstract

Objective
To examine the capacity of IL11 to induce encephalitogenic Th17 cells.

Background
IL11 is the most up-regulated cytokine in the serum and CSF samples from patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). Studies of relapsing remitting experimental autoimmune encephalomyelitis (RREAE), confirmed a causative role of IL11 in worsening clinical severity of the disease and inducing increased numbers of IL17+CD4+ cells within the spinal cord inflammatory infiltrates. Passive transfer RREAE is used to directly examine the role of IL11 in the induction of the encephalitogenic Th17 cells.

Methods
SJL Mice were immunized with PLP139–151, sacrificed at day 11 at the onset of clinical EAE, and LN cells were re-stimulated with: 1) PLP, 2) PLP+IL11, and 3) PLP+IL23 for 7 days. Clinical scores and weight were measured following passive transfer of CD4+ cells daily in three groups for 70 days.

Results
Antigen recall experiments on LN cells revealed that invitro restimulation with PLP 139–151 in the presence of IL11 induces an increased percentage of IL17A+CD4+ cells (17.80%, p&lt;0.001), similar to IL23 (18.33%, p&lt;0.001). Upon passive transfer of CD4+ cells, mice that received IL-11-stimulated cells had an earlier onset of the disease (day 9 vs. 14) and increased average scores compared to mice that received cells restimulated with antigen only (ANOVA, p&lt;0.001). There was no statistically significant difference between the severity of the disease induced by IL11 and IL23-polarized cells.

Conclusion
Our study demonstrated that IL11 induced encephalitogenic Th17 cells, similar to the prototypical Th17 polarizing cytokine IL23.
The study was supported by R03 AI111592-01 grant from NIH/NINDS.