bluuebunny/crossref_metadata_2025_split huggingface dataset:
Understanding the effects of a calorie restriction mimetic on renal cancer progression and CD8 T cell immunity
Authors: Orlandella Rachael M , Boi Shannon , Smith Daniel , Norian Lyse A 
Published: January 2023

Abstract
Metastatic renal cell carcinoma (RCC) exhibits high mortality rates and chemotherapeutic resistance. Immune-based therapies, including high-dose IL-2 and anti-PD1, are efficacious in ~20% of patients; however, both are associated with substantial toxicity. This highlights the need for additional research aimed at improving response rates while also limiting toxicity. Previous findings by other groups have demonstrated that nutrient deprivation prior to chemotherapy reduces treatment toxicity and may improve therapeutic efficacy in cancer patients. Recent murine research shows that diets containing calorie restriction mimetics (CRMs) can recapitulate these beneficial effects by enhancing anti-cancer immunity. Here, we examined the impact of the alpha-glucosidase inhibitor acarbose, a potential CRM, on renal tumor burden and immune profiles. BALB/c mice were fed an acarbose-containing diet or macronutrient-matched control diet for 4 weeks prior to challenge with syngeneic Renca renal carcinoma cells. Although no significant differences were observed in primary renal tumor outgrowth or spontaneous lung metastases (both, p&lt;0.05), acarbose-fed mice exhibited severe weight loss following intra-renal tumor challenge (p=0.02). Tumor-bearing mice fed an acarbose diet displayed increased percentages of total splenic (p=0.03) and intra-tumoral (p=0.04) CD8 T cells versus controls. Future experiments will evaluate the effects of the acarbose CRM on immunotherapeutic efficacy and ensuing immune responses. Our findings demonstrate that further research is required to understand how specific CRMs impact tumor outgrowth and anti-cancer immunity.
Obesity promotes cancer growth by enhancing the suppressive activity of intratumoral myeloid cells
Authors: Al-Ramadi Basel K , Kaimala Suneesh , Mohamed Yassir A. , Al-Sbiei Ashraf , Bashir Ghada , Fernandez-Cabezudo Maria J 
Published: January 2023

Abstract
Epidemiological evidence suggests that obesity is linked to increased risk of developing several types of cancer. However, the mechanisms underlying this phenomenon remain unknown. Successful growth of cancer cells depends on developing mechanisms to evade host immunosurveillance, particularly within the tumor microenvironment. In the current study, we utilized a high-fat-diet (HFD)-induced obese mouse model to gain mechanistic insight into the effect of obesity on progression of implantable syngeneic tumors. When lean or obese mice were implanted with B16.F1 melanoma or MC38 colon carcinoma, tumor growth was more robust in obese group than lean controls, suggesting that obese conditions promote tumor growth. Multi-color flow cytometric analysis and gene expression profiling were carried out on distinct subpopulations of intratumoral myeloid cells. Tumors of lean mice had higher percentages of myeloid cells compared to obese counterparts with characteristics typical of activated inflammatory macrophages. In contrast, tumors of obese mice had disproportionately higher frequency of myeloid derived suppressor cells (MDSC) with a gene signature suggestive of immunosuppressive potential. These findings highlight the role of metaflammation in tumor growth promotion via the regulation of frequency and activation status of distinct subpopulations of intratumoral myeloid cells.
ERK Signaling-regulated Immune Responses that contributes to Malaria Parasitemia and Pathogenesis
Authors: Wu Xianzhu , Dayanand Kiran K. , Thylur Ramesh P , Norbury Christopher C , Gowda Channe 
Published: January 2023

Abstract
Malaria morbidity and mortality represent a major health and social burdens in many countries around the globe. Given that malaria parasites are becoming more and more refractory to several commonly used drugs, a vaccine is needed to control malaria. However, development of an effective vaccine has been hampered due to incomplete understanding of immunological processes and their regulation. We studied the role of ERK1/2 MAPK signaling regulated immune responses by targeting the signaling pathway in P. berghei ANKA-infected mice, an experimental cerebral malaria model. The signaling was targeted using two small molecule inhibitors PD98059 and an FDA approved anti-cancer drug trametinib, both of which specifically inhibit activities of MEK1/MEK2, the upstream kinases of ERK1/2. The results showed that ERK signaling significantly curtails B1 cell expansion, IgM production, phagocytic receptor expression, and phagocytic clearance of parasites, thereby contributing to high parasite burden. The results also showed that ERK1/2 signaling upregulates pro-inflammatory responses and downregulates anti-inflammatory responses, promoting Th1 response and impeding Th2 response. This resulted in increased T cell cytotoxicity and enhanced infiltration of immune cells to the brain, brain vascular damage and dysfunction. Thus, we identified several previously unrecognized immune regulatory processes through which ERK1/2 signaling exacerbates malaria parasitemia and pathogenesis. Our findings highlight how the ERK1/2 signaling-regulated immune responses limit parasite clearance and contribute to severe malaria pathogenesis.
B cells eliminate virus-specific CD8 T cells through a FasL:Fas dependent mechanism during high-dose influenza virus infections.
Authors: Zacharias Zeb Raplh , Legge Kevin L 
Published: January 2023

Abstract
Our prior studies have shown that after high-dose inoculums or infection with high-pathogenic strains of influenza A virus (IAV), the IAV-specific CD8 T cell response is targeted and killed by plasmacytoid dendritic cells (pDCs) within the draining lymph nodes (LN) in a FasL:Fas (pDC:T cells) dependent manner. This limits host immunity and drives severe disease. Although donor pDCs are sufficient to drive this response in FasL defective gld mice, our recent findings show that FasL+ B cells out number FasL+ pDCs 50:1 within the LN during high-dose IAV infections. This suggested that B cells might contribute to the overall loss of CD8 T cells during high-dose/high-pathogenic IAV infections. Further, we have identified at least two subsets of FasL+ B cells (i.e. CD11c+ and CD11c−) that accumulate at higher numbers within the LN following high- vs. low-dose IAV infections. Additionally, our results suggest that FasL expression by CD11c+ and CD11c− B cells is induced in part by IL-12p40, which is expressed at higher levels in the LN during high-dose IAV infections. Finally, adoptive transfer studies utilizing gld host mice demonstrate that both donor CD11c+ and CD11c− B cell subsets can eliminate IAV-specific CD8 T cells in a FasL:Fas dependent manner during high-dose IAV infections. Therefore overall it appears that FasL+ B cells contribute to the loss of IAV-specific CD8 T cells during high-dose IAV infections ultimately leading to the death of the host.
The complement receptor CRIg dominates clearance of intravascular parasites during African trypanosome infection
Authors: Liu Gongguan , Sun Peng , Xu Jinjun , Shi Meiqing 
Published: January 2023

Abstract
Kupffer cells (KCs), the liver resident macrophages, play a prominent role in clearance of blood-borne pathogens. The mechanisms by which KCs engulf circulating parasites such as African trypanosomes have yet to be determined. Here we show that depletion of KCs resulted in uncontrolled parasitemia in mice infected with Trypanosoma congolense, indicating the essential role of KCs in clearance of intravascular parasites. By using intravital microscopy, we further investigated the dynamics of interactions of KCs with circulating T. congolense in real-time. The results demonstrate that KCs catch circulating parasites in the presence of specific IgM and IgG antibodies, but fail to do so in the absence of specific antibodies. Complement C3 is critically involved in the capture of the parasites mediated by both IgM and IgG. We further demonstrate that complement receptor CRIg, but not CR3, is crucial for KCs to catch the parasites. In support of the findings gained by in vivo imaging, mice deficient of C3 or CRIg, but not CR3, could not control the first wave of parasitemia, and had a dramatic reduced survival time compared to wild-type mice following infection with T. congolense (10 days vs over 100 days). Collectively, our data demonstrate that CRIg play a dominant role in the clearance of circulating parasites by KCs in an antibody dependent manner.
Brucella melitensis specifically interferes with autophagy pathway in human monocytes and enhances anti-inflammatory response.
Authors: Paliogianni Fotini , Giannopoulou Ioanna , Liopeta Kassiani , Sanoudou Despoina , Dimitrakopoulos Odyssefs 
Published: January 2023

Abstract
Autophagy and cytokine response are both involved in host defense against intracellular bacteria, including Brucella. However the effect of autophagy on the balance of Brucella triggered pro- and anti-inflammatory cytokine production has not been studied in the human system. In the present study, we assessed the effect of autophagy on pro- and anti-inflammatory cytokine production, using primary human monocytes infected with live clinical strain of B. melitensis in the presence or absence of specific autophagy inhibitors (Wortmannin, LY294002). Autophagy inhibition resulted in significant induction mainly of IL-1b and TNF-a release as detected at the cell culture supernatants after 16h of stimulation. The effect was less prominent on IL-6 production. Most importantly IL-10 production was drastically reduced in the presence of autophagy inhibitors. Activation of specific autophagy proteins in THP-1 cells infected with B. melitensis was detected at different time points of infection. Differentiation of THP-1 cells to macrophage phenotype induced autophagy as detected by the formation of LC3II complex. Prolonged stimulation with B. melitensis (2–24h) neither altered the formation of LC3II complex nor affected the amount of ULK1 protein. Microarray analysis of the transcriptional response of peripheral human monocytes 4h postinfection with B. melitensis, revealed a dramatic increase of a protein upstream of LC3II that has an essential role in regulation of autophagy. These results suggest that autophagy differentially regulates cytokine response against B. melitensis in humans, modulating inflammation probably by interfering in signaling pathways initiated by key autophagy proteins.
Partial role of CXCR3 in the migration of CD4 T cells into the lung of TB infected mice
Authors: Hoft Stella G , Sallin Michelle A , Sakai Shunsuke , Barber Daniel L 
Published: January 2023

Abstract
Mycobacterium tuberculosis (Mtb) is the leading cause of death by infectious disease worldwide. In order to develop effective vaccination strategies for Mtb, it is critical to understand the properties of host-protective CD4 T cells. We have shown that various subsets of Mtb-specific Th1 cells display dramatically different lung migratory abilities. CXCR3+ Th1 cells migrate into the lung and control Mtb infection, while CX3CR1+ Th1 cells are retained in the lung-associated blood vasculature and do not suppress bacterial growth in vivo. However, little is know about the precise role of different chemokine receptors in the entry of Mtb-specific Th1 cells into the lung. Here we quantify the individual contributions of several chemokine receptors in the pulmonary migration of Th1 cells by performing in vivo migration experiments after adoptive transfer of WT and CCR KO Mtb-specific lung effector T cells into infection matched WT recipients. Firstly, we find that Th1 cells migration into the lung is pertussis toxin sensitive, indicating that G-protein coupled receptors are required. We find that while CXCR6 is highly expressed in Th1 cells capable of migrating into the lung, it has no role in their entry. Likewise, CCR2 had no role in Th1 cell migration into Mtb infected lungs. Interestingly, CXCR3−/− CD4 T cells displayed only a ~30% reduction compared to WT cells 16 hours after transfer. Although CXCR3 and CXCR6 are defining markers expressed on all lung-homing Mtb-specific Th1 cells, our results indicate that additional chemokine receptors are involved in their migration. Identification of new mechanisms governing the migration of Mtb-specific Th1 cells into the lung may give important insight into T cell dependent immunity to Mtb infection.
TACI contributes to Plasmodium yoelii host resistance by controlling the kinetics of Tfh and GC formation and antibody development
Authors: Parra Marcela , Yang Jiyeon , Schmidt Thomas , Derrick Steven , Yang Amy , Liu Xia , Siddiqui Shafiuddin , Akkoyunlu Mustafa 
Published: January 2023

Abstract
The transmembrane activator and calcium-modulator and cyclophilin ligand receptor (TACI) is involved in B-cell survival, antibody isotype switching and plasma cell generation. TACI expression is severely impaired in murine and human newborns as compared to adults. We challenged TACI knock-out (KO)-mice with Plasmodium yoelii (Py) NL in order to evaluate the role of TACI in response to malaria infection. We found that the parasitemia levels were significantly elevated in TACI KO-mice (61.8% at day 18) compared to WT-mice (11.1% at day 11), and that parasite clearance was substantially delayed in the TACI KO (27 days) mice relative to WT controls (18 days). We also determined that TACI KO-mice have a delay in anti-Py NL IgG-antibody production when compared with the WT-mice. Since the interaction of T follicular helper (Tfh) cells with antigen specific B cells in the germinal center (GC) is essential for the generation of antibody responses, we measured the formation of Tfh and GC in the spleens of Py NL infected mice. Interestingly, we determined that while Tfh cell numbers were elevated on day 10 in both the strains, WT mice Tfh cell numbers sharply declined by day 15 as the number of Tfh cells in TACI KO-mice remained high. Coinciding with parasite clearance, TACI KO Tfh cells declined to baseline values on day 25 and GC B cells remained high beyond day 15 when WT GC B cells declined. Finally, we detected elevated serum levels of the TACI ligand B cell-activating factor belonging to the TNF family (BAFF) in infected TACI KO mice as compared to the WT mice. In conclusion, susceptibility of TACI deficient mice to Py NL infection appears to be based on altered Tfh and GC kinetics, which in turn results in delayed antibody development.
The m153 gene product stabilizes expression of the inhibitory NKR-P1B ligand, Clr-b, during mouse cytomegalovirus infection
Authors: Aguilar Oscar A , Rahim Mir Munir A , Sampaio Isabella S , Samaniego Jackeline D , Popović Branka , Tilahun Mulualem E , Krmpotić Astrid , Margulies David H , Allan David S.J. , Makrigiannis Andrew , Jonjić Stipan , Carlyle James R 
Published: January 2023

Abstract
Natural killer (NK) cells are a subset of innate lymphoid cells (ILC) capable of recognizing stressed and infected cells through multiple germline-encoded receptor-ligand interactions. Missing-self recognition involves NK cell sensing of the loss of host-encoded inhibitory ligands on target cells, including MHC class I (MHC-I) molecules and MHC-independent ligands. Mouse cytomegalovirus (MCMV) infection has been shown to promote a rapid loss of the inhibitory NKR-P1B ligand, Clr-b, on infected cells. Here, we provide evidence that an MCMV m145 family member, m153, functions to stabilize Clr-b at the cell surface during MCMV infection. Ectopic expression of m153 in fibroblasts significantly augments Clr-b cell surface levels. Moreover, infections using m153-deficient MCMV mutants (Δm144-m158; Δm153) show an accelerated and exacerbated Clr-b downregulation. Importantly, enhanced loss of Clr-b upon infection with MCMV Δm153-mutants can be reverted to wild-type levels by exogenous m153 complementation in fibroblasts. While the effects of m153 on Clr-b levels are independent of Clec2d transcription, imaging experiments reveal that the m153 and Clr-b proteins only minimally co-localize within the same subcellular compartments, and tagged versions of the proteins were refractory to co-immunoprecipitation using gentle detergents. Indeed, a prominent intracellular vesicular localization of m153 suggests that its effects on Clr-b stabilization may be indirect. In vivo, the Δm153-mutant possesses enhanced virulence, independent of Clr-b and NKR-P1B, suggesting that m153 may modulate other Clr or activating NKR:ligand interactions.
Transgenic West Nile Virus virus-specific CD8+ T cells provide insights on activation patterns and protective role of cytotoxic T cells during infection
Authors: Aguilar-Valenzuela Renan , Seo Young-Jin , Grakoui Arash , Suthar Mehul S 
Published: January 2023

Abstract
West Nile Virus (WNV) is the leading cause of mosquito-borne encephalitis worldwide. Currently, there are no vaccines or therapeutics approved for use in humans. Virus-specific CD8+ T cells are essential in mediating protective immunity during WNV infection. However, the mechanisms that promote protective CD8+ T cell immunity against WNV are not well understood. In this study, we characterized a novel transgenic mouse encoding CD8+ T cells to the immunodominant epitope located within the WNV NS4b protein (WNV-I). Through adoptive transfer studies in mice, we evaluated the expansion, migration, and functional properties of WNV-I CD8+ T cells during infection. In the spleen, WNV-I CD8+ T cell numbers increased on day 7 post-infection followed by contraction in cell numbers through day 15 post-infection. We observed a robust infiltration of virus-specific CD8+ T cells to the brain on day 7 concomitant with an increase in virus replication within the CNS. Interestingly, we observed clearance of infectious virus from the brain, however, WNV-I CD8+ T cells remained elevated in the brain through day 15 post-infection. Functionally, WNV-I CD8+ T cells secrete both IFN-γ and TNF-α, with peak responses in the spleen and in the brain on days 7 and 11 post-infection, respectively. Furthermore, Rag-1−/− mice that received WNV-I CD8+ T cells had lower viral burden in spleens and serum at day 7 of infection. Thus, WNV-I cells are functionally active and can mediate protective immunity against WNV infection. Further studies are underway to better understand how CD8+ T cells mediate WNV clearance in the central nervous system.
The CD4 T cell response in acute infection with dengue virus
Authors: Weiskopf Daniela , de-Oliveira-Pinto Luzia M , Tian Yuan , de Silva Aruna D , Seumois Gregory , Vijayanand Pandurangan , Premawansa Sunil , Premawansa Gayani , Wijewickrama Ananda , Peters Bjoern , Sette Alessandro 
Published: January 2023

Abstract
Dengue virus (DENV) is the etiologic agent of dengue fever (DF), the most significant mosquito-borne viral disease in humans. DENV transmission occurs in more than 100 countries and is an increasing public health problem in tropical and sub-tropical regions. Up to 400 million DENV infections occur every year and severity can range from asymptomatic to an acute self-limiting febrile illness (DF) or the more severe hemorrhagic fever (DHF) characterized by severe vascular leakage, thrombocytopenia, and hemorrhagic manifestations. In this study we have investigated the acute CD4+ T cell response in hospitalized patients with different severity of disease manifestations. Samples from patients either diagnosed with DF or DHF have been collected in the acute phase and in the convalescent phase after resolving the infection. Virus specific CD4 T cells were detected based on their ability to produce cytokines in response to stimulation with DENV specific peptide pools in an intracellular cytokine assay. All donors elicited IFNγ in the convalescent phase of infection, regardless of the severity of disease. Interestingly, in the acute phase DF patients elicited IFNγ in response to the peptide pool, while the response in DHF patients was dominated by IL-10. Further characterization revealed that these responding IFNγ and IL 10 producing CD4 T cells differ in memory phenotype as well as activation markers. We are currently establishing specific gene expression signatures, associated with these characteristic phenotypes. Detailed knowledge of phenotype and function of DENV specific T cells will aid in the establishment of correlates of protection against severe disease.
Immune signatures of CD4 T cell subsets in healthy and dengue virus-infected individuals
Authors: Tian Yuan , Babor Mariana , Seumois Gregory , Vijayanand Pandurangan , Weiskopf Daniela , Peters Bjoern , Sette Alessandro 
Published: January 2023

Abstract
Dengue virus (DENV) has spread through most tropical and subtropical areas of the world and represents a serious public health problem. The control of DENV infections has been hindered by lack of effective therapeutics or vaccines. Nevertheless, a better understanding of the immune system both at steady state and following DENV infections may reveal new strategies for eliciting and improving anti-DENV immunity. T cells provide protective immunity against various viral infections, and recent findings demonstrate that a subset of CD4 T cells, designated effector memory re-expressing CD45RA T (Temra) cells, expand following DENV infections and may play an important role in protecting the host from severe dengue diseases. In this study, we report that CD4 Temra cells display unique gene expression profiles characterized by the upregulation of cytotoxic molecules such as perforin, granzyme B and GPR56, as well as transcription factors including T-bet, Eomes, Runx3 and Hobit, which direct T cell differentiation, function and tissue residency. Furthermore, our results indicate that CD4 Temra cells are heterogeneous and can be largely divided into two sub-populations, which exhibited differential expression of various effector molecules and transcriptional regulators. Finally, using high-dimensional mass cytometry, we further dissected the heterogeneity of DENV-specific CD4 Temra cells. Over 30 molecules were analyzed simultaneously, resulting in the identification of novel subsets within the CD4 Temra population. Overall, our findings reveal immune signatures of CD4 Temra cells in healthy and DENV-infected individuals and provide new insights into the antiviral immunity against DENV and potentially other emerging pathogens.