Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 11 to 20 of 367

Publication Record

Connections

Links between Immunologic Memory and Metabolic Cycling.
Cottam MA, Itani HA, Beasley AA, Hasty AH
(2018) J Immunol 200: 3681-3689
MeSH Terms: Adaptive Immunity, Animals, Body Weight, Humans, Hypertension, Immunity, Innate, Immunologic Memory, Metabolic Diseases
Show Abstract · Added March 26, 2019
Treatments for metabolic diseases, such as diet and therapeutics, often provide short-term therapy for metabolic stressors, but relapse is common. Repeated bouts of exposure to, and relief from, metabolic stimuli results in a phenomenon we call "metabolic cycling." Recent human and rodent data suggest metabolic cycling promotes an exaggerated response and ultimately worsened metabolic health. This is particularly evident with cycling of body weight and hypertension. The innate and adaptive immune systems have a profound impact on development of metabolic disease, and current data suggest that immunologic memory may partially explain this association, especially in the context of metabolic cycling. In this Brief Review, we highlight recent work in this field and discuss potential immunologic mechanisms for worsened disease prognosis in individuals who experience metabolic cycling.
Copyright © 2018 by The American Association of Immunologists, Inc.
0 Communities
1 Members
0 Resources
8 MeSH Terms
The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism.
Fensterheim BA, Young JD, Luan L, Kleinbard RR, Stothers CL, Patil NK, McAtee-Pereira AG, Guo Y, Trenary I, Hernandez A, Fults JB, Williams DL, Sherwood ER, Bohannon JK
(2018) J Immunol 200: 3777-3789
MeSH Terms: Adenosine Triphosphate, Animals, Candida albicans, Candidiasis, Glycolysis, Lipid A, Macrophages, Male, Mice, Mice, Inbred C57BL, Myeloid Differentiation Factor 88, Signal Transduction, Staphylococcal Infections, Staphylococcus aureus, TOR Serine-Threonine Kinases, Toll-Like Receptor 4
Show Abstract · Added March 28, 2019
Monophosphoryl lipid A (MPLA) is a clinically used TLR4 agonist that has been found to drive nonspecific resistance to infection for up to 2 wk. However, the molecular mechanisms conferring protection are not well understood. In this study, we found that MPLA prompts resistance to infection, in part, by inducing a sustained and dynamic metabolic program in macrophages that supports improved pathogen clearance. Mice treated with MPLA had enhanced resistance to infection with and that was associated with augmented microbial clearance and organ protection. Tissue macrophages, which exhibited augmented phagocytosis and respiratory burst after MPLA treatment, were required for the beneficial effects of MPLA. Further analysis of the macrophage phenotype revealed that early TLR4-driven aerobic glycolysis was later coupled with mitochondrial biogenesis, enhanced malate shuttling, and increased mitochondrial ATP production. This metabolic program was initiated by overlapping and redundant contributions of MyD88- and TRIF-dependent signaling pathways as well as downstream mTOR activation. Blockade of mTOR signaling inhibited the development of the metabolic and functional macrophage phenotype and ablated MPLA-induced resistance to infection in vivo. Our findings reveal that MPLA drives macrophage metabolic reprogramming that evolves over a period of days to support a macrophage phenotype highly effective at mediating microbe clearance and that this results in nonspecific resistance to infection.
Copyright © 2018 by The American Association of Immunologists, Inc.
0 Communities
3 Members
0 Resources
16 MeSH Terms
B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity.
Raybuck AL, Cho SH, Li J, Rogers MC, Lee K, Williams CL, Shlomchik M, Thomas JW, Chen J, Williams JV, Boothby MR
(2018) J Immunol 200: 2627-2639
MeSH Terms: Animals, B-Lymphocytes, Cell Differentiation, Gene Expression, Germinal Center, Immunity, Humoral, Immunoglobulin G, Immunologic Memory, Lymphocyte Activation, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Mutation, Plasma Cells, Proto-Oncogene Proteins c-bcl-6, Signal Transduction, Transcription Factors
Show Abstract · Added March 14, 2018
B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within these lymphoid microenvironments and can influence signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell-intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6-a key transcriptional regulator of the germinal center (GC) fate-in activated B lymphocytes. Accordingly, disruption of mTORC1 after B cell development and activation led to reduced populations of Ag-specific memory B cells as well as plasma cells and GC B cells. In addition, induction of the germ line transcript that guides activation-induced deaminase in selection of the IgG1 H chain region during class switching required mTORC1. Expression of the somatic mutator activation-induced deaminase was reduced by a lack of mTORC1 in B cells, whereas point mutation frequencies in Ag-specific GC-phenotype B cells were only halved. These effects culminated in a B cell-intrinsic defect that impacted an antiviral Ab response and drastically impaired generation of high-affinity IgG1. Collectively, these data establish that mTORC1 governs critical B cell-intrinsic mechanisms essential for establishment of GC differentiation and effective Ab production.
Copyright © 2018 by The American Association of Immunologists, Inc.
1 Communities
2 Members
0 Resources
17 MeSH Terms
Bruton's Tyrosine Kinase Is Not Essential for B Cell Survival beyond Early Developmental Stages.
Nyhoff LE, Clark ES, Barron BL, Bonami RH, Khan WN, Kendall PL
(2018) J Immunol 200: 2352-2361
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, Autoimmune Diseases, B-Lymphocyte Subsets, Cell Survival, Cells, Cultured, Immunoglobulin M, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Antigen, B-Cell, Signal Transduction
Show Abstract · Added March 3, 2020
Bruton's tyrosine kinase (Btk) is a crucial regulator of B cell signaling and is a therapeutic target for lymphoma and autoimmune disease. BTK-deficient patients suffer from humoral immunodeficiency, as their B cells fail to progress beyond the bone marrow. However, the role of Btk in fully developed, mature peripheral B cells is not well understood. Analysis using BTK inhibitors is complicated by suboptimal inhibition, off-target effects, or failure to eliminate BTK's adaptor function. Therefore a mouse model was developed and used to excise after B cell populations were established. Mice lacking from birth are known to have reduced follicular (FO) compartments, with expanded transitional populations, suggesting a block in development. In adult mice, excision did not reduce FO B cells, which persisted for weeks. Autoimmune-prone B1 cells also survived conditional excision, contrasting their near absence in global -deficient mice. Therefore, Btk supports BCR signaling during selection into the FO and B1 compartments, but is not needed to maintain these cell populations. B1-related natural IgM levels remained normal, contrasting global deficiency, but B cell proliferation and T-independent type II immunization responses were blunted. Thus, B cells have nuanced signaling responses that are differentially regulated by Btk for development, survival, and function. These findings raise the possibility that Btk may also be expendable for survival of mature human B cells, therefore requiring prolonged dosing to be effective, and that success of BTK inhibitors may depend in part on off-target effects.
Copyright © 2018 by The American Association of Immunologists, Inc.
0 Communities
1 Members
0 Resources
MeSH Terms
mPGES1-Dependent Prostaglandin E (PGE) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE Production.
Maseda D, Johnson EM, Nyhoff LE, Baron B, Kojima F, Wilhelm AJ, Ward MR, Woodward JG, Brand DD, Crofford LJ
(2018) J Immunol 200: 725-736
MeSH Terms: Animals, Autocrine Communication, Dinoprostone, Epitopes, T-Lymphocyte, Gene Expression Regulation, Immunization, Immunomodulation, Lymphocyte Activation, Mice, Paracrine Communication, Phenotype, Prostaglandin-E Synthases, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Th1 Cells, Th17 Cells
Show Abstract · Added March 25, 2020
The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE, are critical molecules in the initiation and resolution of inflammation and in the transition from innate to acquired immune responses. Microsomal PGE synthase 1 (mPGES1) is an integral membrane enzyme whose regulated expression controls PGE levels and is highly expressed at sites of inflammation. PGE is also associated with modulation of autoimmunity through altering the IL-23/IL-17 axis and regulatory T cell (Treg) development. During a type II collagen-CFA immunization response, lack of mPGES1 impaired the numbers of CD4 regulatory (Treg) and Th17 cells in the draining lymph nodes. Ag-experienced mPGES1 CD4 cells showed impaired IL-17A, IFN-γ, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE by cocultured APCs synergized with that of Ag-experienced CD4 T cells, with mPGES1 competence in the APC compartment enhancing CD4 IL-17A and IFN-γ responses. However, in contrast with CD4 cells that were Ag primed in vivo, exogenous PGE inhibited proliferation and skewed IL-17A to IFN-γ production under Th17 polarization of naive T cells in vitro. We conclude that mPGES1 is necessary in vivo to mount optimal Treg and Th17 responses during an Ag-driven primary immune response. Furthermore, we uncover a coordination of autocrine and paracrine mPGES1-driven PGE production that impacts effector T cell IL-17A and IFN-γ responses.
Copyright © 2018 by The American Association of Immunologists, Inc.
0 Communities
1 Members
0 Resources
MeSH Terms
Cytomegalovirus (CMV) Epitope-Specific CD4 T Cells Are Inflated in HIV CMV Subjects.
Abana CO, Pilkinton MA, Gaudieri S, Chopra A, McDonnell WJ, Wanjalla C, Barnett L, Gangula R, Hager C, Jung DK, Engelhardt BG, Jagasia MH, Klenerman P, Phillips EJ, Koelle DM, Kalams SA, Mallal SA
(2017) J Immunol 199: 3187-3201
MeSH Terms: ADP-ribosyl Cyclase 1, CD4-Positive T-Lymphocytes, Cytomegalovirus, Cytomegalovirus Infections, Epitopes, T-Lymphocyte, Female, HIV Infections, HIV-1, HLA-DR7 Antigen, Humans, Immunologic Memory, Male, Membrane Glycoproteins, Viral Proteins
Show Abstract · Added March 30, 2020
Select CMV epitopes drive life-long CD8 T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4 T cells specific for human CMV (HCMV) are elevated in HIV HCMV subjects. To determine whether HCMV epitope-specific CD4 T cell memory inflation occurs during HIV infection, we used HLA-DR7 (DRB1*07:01) tetramers loaded with the glycoprotein B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4 T cells in coinfected HLA-DR7 long-term nonprogressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4 T cells were inflated among these HIV subjects compared with those from an HIV HCMV HLA-DR7 cohort or with HLA-DR7-restricted CD4 T cells from the HIV-coinfected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, EBV nuclear Ag 2, or HIV gag protein. Inflated DYS-specific CD4 T cells consisted of effector memory or effector memory-RA subsets with restricted TCRβ usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near-monoclonal TCR in a Jurkat cell-transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme B, CXCR1, CD38, or HLA-DR but less often coexpressed CD38 and HLA-DR The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4 T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease.
Copyright © 2017 by The American Association of Immunologists, Inc.
0 Communities
1 Members
0 Resources
MeSH Terms
In Utero Exposure to Histological Chorioamnionitis Primes the Exometabolomic Profiles of Preterm CD4 T Lymphocytes.
Matta P, Sherrod SD, Marasco CC, Moore DJ, McLean JA, Weitkamp JH
(2017) J Immunol 199: 3074-3085
MeSH Terms: Biomarkers, Chorioamnionitis, Enterotoxins, Female, Humans, Infant, Newborn, Infant, Premature, Male, Pregnancy, Th1 Cells
Show Abstract · Added September 28, 2017
Histological chorioamnionitis (HCA) is an intrauterine inflammatory condition that increases the risk for preterm birth, death, and disability because of persistent systemic and localized inflammation. The immunological mechanisms sustaining this response in the preterm newborn remain unclear. We sought to determine the consequences of HCA exposure on the fetal CD4 T lymphocyte exometabolome. We cultured naive CD4 T lymphocytes from HCA-positive and -negative preterm infants matched for gestational age, sex, race, prenatal steroid exposure, and delivery mode. We collected conditioned media samples before and after a 6-h in vitro activation of naive CD4 T lymphocytes with soluble staphylococcal enterotoxin B and anti-CD28. We analyzed samples by ultraperformance liquid chromatography ion mobility-mass spectrometry. We determined the impact of HCA on the CD4 T lymphocyte exometabolome and identified potential biomarker metabolites by multivariate statistical analyses. We discovered that: 1) CD4 T lymphocytes exposed to HCA exhibit divergent exometabolomic profiles in both naive and activated states; 2) ∼30% of detected metabolites differentially expressed in response to activation were unique to HCA-positive CD4 T lymphocytes; 3) metabolic pathways associated with glutathione detoxification and tryptophan degradation were altered in HCA-positive CD4 T lymphocytes; and 4) flow cytometry and cytokine analyses suggested a bias toward a T1-biased immune response in HCA-positive samples. HCA exposure primes the neonatal adaptive immune processes by inducing changes to the exometabolomic profile of fetal CD4 T lymphocytes. These exometabolomic changes may link HCA exposure to T1 polarization of the neonatal adaptive immune response.
Copyright © 2017 by The American Association of Immunologists, Inc.
1 Communities
2 Members
0 Resources
10 MeSH Terms
The Cytokine Response to Lipopolysaccharide Does Not Predict the Host Response to Infection.
Fensterheim BA, Guo Y, Sherwood ER, Bohannon JK
(2017) J Immunol 198: 3264-3273
MeSH Terms: Animals, Cytokines, Disease Models, Animal, Flow Cytometry, Ligands, Lipid A, Lipopolysaccharides, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Poly I-C, Pseudomonas Infections, Pseudomonas aeruginosa, Toll-Like Receptors
Show Abstract · Added April 10, 2017
The magnitude of the LPS-elicited cytokine response is commonly used to assess immune function in critically ill patients. A suppressed response, known as endotoxin tolerance, is associated with worse outcomes, yet endotoxin tolerance-inducing TLR4 ligands are known to protect animals from infection. Thus, it remains unknown whether the magnitude of the LPS-elicited cytokine response provides an accurate assessment of antimicrobial immunity. To address this, the ability of diverse TLR ligands to modify the LPS-elicited cytokine response and resistance to infection were assessed. Priming of mice with LPS, monophosphoryl lipid A (MPLA), or poly(I:C) significantly reduced plasma LPS-elicited proinflammatory cytokines, reflecting endotoxin tolerance, whereas CpG-ODN-primed mice showed augmented cytokine production. In contrast, LPS, MPLA, and CpG-ODN, but not poly(I:C), improved the host response to a infection. Mice primed with protective TLR ligands, including CpG-ODN, showed reduced plasma cytokines during infection. The protection imparted by TLR ligands persisted for up to 15 d yet was independent of the adaptive immune system. In bone marrow-derived macrophages, protective TLR ligands induced a persistent metabolic phenotype characterized by elevated glycolysis and oxidative metabolism as well as augmented size, granularity, phagocytosis, and respiratory burst. Sustained augmentation of glycolysis in TLR-primed cells was dependent, in part, on hypoxia-inducible factor 1-α and was essential for increased phagocytosis. In conclusion, the magnitude of LPS-elicited cytokine production is not indicative of antimicrobial immunity after exposure to TLR ligands. Additionally, protective TLR ligands induce sustained augmentation of phagocyte metabolism and antimicrobial function.
Copyright © 2017 by The American Association of Immunologists, Inc.
0 Communities
2 Members
0 Resources
15 MeSH Terms
The Molecular Basis for the Lack of Inflammatory Responses in Mouse Embryonic Stem Cells and Their Differentiated Cells.
D'Angelo W, Gurung C, Acharya D, Chen B, Ortolano N, Gama V, Bai F, Guo YL
(2017) J Immunol 198: 2147-2155
MeSH Terms: Animals, Cell Differentiation, Chikungunya Fever, Chikungunya virus, Embryonic Stem Cells, Immunity, Inflammation, Interferons, Lipopolysaccharides, Mice, Mice, Inbred DBA, NF-kappa B, RAW 264.7 Cells, Tumor Necrosis Factor-alpha, Virus Diseases
Show Abstract · Added July 10, 2017
We reported previously that mouse embryonic stem cells do not have a functional IFN-based antiviral mechanism. The current study extends our investigation to the inflammatory response in mouse embryonic stem cells and mouse embryonic stem cell-differentiated cells. We demonstrate that LPS, TNF-α, and viral infection, all of which induce robust inflammatory responses in naturally differentiated cells, failed to activate NF-κB, the key transcription factor that mediates inflammatory responses, and were unable to induce the expression of inflammatory genes in mouse embryonic stem cells. Similar results were obtained in human embryonic stem cells. In addition to the inactive state of NF-κB, the deficiency in the inflammatory response in mouse embryonic stem cells is also attributed to the lack of functional receptors for LPS and TNF-α. In vitro differentiation can trigger the development of the inflammatory response mechanism, as indicated by the transition of NF-κB from its inactive to active state. However, a limited response to TNF-α and viral infection, but not to LPS, was observed in mouse embryonic stem cell-differentiated fibroblasts. We conclude that the inflammatory response mechanism is not active in mouse embryonic stem cells, and in vitro differentiation promotes only partial development of this mechanism. Together with our previous studies, the findings described in this article demonstrate that embryonic stem cells are fundamentally different from differentiated somatic cells in their innate immunity, which may have important implications in developmental biology, immunology, and embryonic stem cell-based regenerative medicine.
Copyright © 2017 by The American Association of Immunologists, Inc.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Oxidized Low-Density Lipoprotein Immune Complex Priming of the Nlrp3 Inflammasome Involves TLR and FcγR Cooperation and Is Dependent on CARD9.
Rhoads JP, Lukens JR, Wilhelm AJ, Moore JL, Mendez-Fernandez Y, Kanneganti TD, Major AS
(2017) J Immunol 198: 2105-2114
MeSH Terms: Animals, Antibodies, Antigen-Antibody Complex, CARD Signaling Adaptor Proteins, Cells, Cultured, Cytokines, Dendritic Cells, Inflammasomes, Inflammation Mediators, Lipoproteins, LDL, Macrophages, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein, Receptor Cross-Talk, Receptors, IgG, Signal Transduction, Th17 Cells, Toll-Like Receptors
Show Abstract · Added March 30, 2020
Oxidized low-density lipoprotein (oxLDL) is known to activate inflammatory responses in a variety of cells, especially macrophages and dendritic cells. Interestingly, much of the oxLDL in circulation is complexed to Abs, and these resulting immune complexes (ICs) are a prominent feature of chronic inflammatory disease, such as atherosclerosis, type-2 diabetes, systemic lupus erythematosus, and rheumatoid arthritis. Levels of oxLDL ICs often correlate with disease severity, and studies demonstrated that oxLDL ICs elicit potent inflammatory responses in macrophages. In this article, we show that bone marrow-derived dendritic cells (BMDCs) incubated with oxLDL ICs for 24 h secrete significantly more IL-1β compared with BMDCs treated with free oxLDL, whereas there was no difference in levels of TNF-α or IL-6. Treatment of BMDCs with oxLDL ICs increased expression of inflammasome-related genes , , and , and pretreatment with a caspase 1 inhibitor decreased IL-1β secretion in response to oxLDL ICs. This inflammasome priming was due to oxLDL IC signaling via multiple receptors, because inhibition of CD36, TLR4, and FcγR significantly decreased IL-1β secretion in response to oxLDL ICs. Signaling through these receptors converged on the adaptor protein CARD9, a component of the CARD9-Bcl10-MALT1 signalosome complex involved in NF-κB translocation. Finally, oxLDL IC-mediated IL-1β production resulted in increased Th17 polarization and cytokine secretion. Collectively, these data demonstrate that oxLDL ICs induce inflammasome activation through a separate and more robust mechanism than oxLDL alone and that these ICs may be immunomodulatory in chronic disease and not just biomarkers of severity.
Copyright © 2017 by The American Association of Immunologists, Inc.
0 Communities
1 Members
0 Resources
MeSH Terms