Abstract Bcl-2 plays a critical role in regulating cell survival and apoptosis. We examined expression virus-specific CD8 T cells during the expansion, death, memory phases of response following infection mice with lymphocytic choriomeningitis virus (LCMV). Naive expressed basal level that was down-regulated effector just before death phase. levels remained low phase but surviving higher than naive cells. These changes were shown to occur LCMV TCR transgenic as well C57BL/6 BALB/c identified...

Abstract Apoptosis is a critical regulator of homeostasis in the immune system. In this study we demonstrate that memory CD8+ T cells are more resistant to apoptosis than naive cells. After whole body irradiation mice, both and decreased number, but reduction number was 8-fold greater addition examining radiation-induced apoptosis, analyzed expansion contraction vivo following exposure Ag. We found not only responded quickly after viral infection, secondary effector generated from underwent...

Significance The TREX1 enzyme degrades DNA, and mutations in the gene cause autoimmune diseases. D18N mutation causes a form of lupus called familial chilblain lupus. We solved structure bound to dsDNA, showing how interacts with dsDNA. also replaced WT mice mutated showed this lupus-like disease. Together, D18N–dsDNA spontaneous disease exhibited mouse help define dsDNA prevent molecule from acting as an autoantigen and, most likely, humans promote

The immune system is complex, with multiple layers of regulation that serve to prevent the production self-antigens. One layer involves regulatory T cells (Tregs) play an essential role in maintaining peripheral self-tolerance. Patients autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis have decreased levels HDL, suggesting apoA-I concentrations may be important preventing autoimmunity loss In published studies, hypercholesterolemic mice lacking HDL or...

The purpose of this study was to determine the effects an atherogenic diet on immune function in LDLr(-/-), ApoA-I(-/-) mice.When (DKO), and LDLr(-/-) (SKO) mice were fed diet, DKO had larger peripheral lymph nodes (LNs) spleens compared SKO mice. LNs enriched cholesterol contain expanded populations T, B, dendritic cells, macrophages. Expansion all classes LN cells accompanied by a approximately 1.5-fold increase T cell proliferation activation. Plasma antibodies dsDNA, beta2-glycoprotein...

Abstract Reactive oxygen intermediates (ROI) generated in response to receptor stimulation play an important role mediating cellular responses. We have examined the importance of reversible cysteine sulfenic acid formation naive CD8+ T cell activation and proliferation. observed that, within minutes activation, cells increased ROI levels a manner dependent upon Ag concentration. Increased resulted elevated total proteome. Analysis specific proteins revealed that protein tyrosine phosphatases...

Mutations in the TREX1 3’ → 5’ exonuclease are associated with a spectrum of autoimmune disease phenotypes humans and mice. Failure to degrade DNA activates cGAS-STING DNA-sensing pathway signaling type-I interferon (IFN) response that ultimately drives immune system activation. have also been implicated tumor microenvironment, where is proposed tumor-derived would otherwise activate cGAS-STING. If were not degraded, be activated promote IFN-dependent antitumor immunity. Thus, we hypothesize...

Abstract Following infection with intracellular pathogens, Ag-specific CD8+ T cells become activated and begin to proliferate. As these activated, they elaborate effector functions including cytokine production cytolysis. After the has been cleared, immune system returns homeostasis through apoptosis of majority cells. The surviving memory can persist for extended periods provide protection against reinfection. Little is known about changes in gene expression as progress stages development,...

Abstract Although androgen ablation therapy is effective in treating primary prostate cancers, a significant number of patients develop incurable castration-resistant disease. Recent studies have suggested potential synergy between vaccination and ablation, yet the enhanced T-cell function transient. Using defined tumor antigen model, UV-8101-RE, we found that concomitant castration significantly increased frequency antigen-specific CD8+ T cells early after immunization wild-type mice....

Apoptosis is critical for the development and maintenance of immune system. The proapoptotic Bcl-2 family member Bim important normal system homeostasis. Although previous experiments have shown that apoptosis antigen-specific CD8(+) T cells during acute viral infection, role chronic infection unclear. Using lymphocytic choriomeningitis virus clone 13 mice, we demonstrate a in T-cell infection. Enumeration by major histocompatibility complex class I tetramer staining revealed...

Abstract After Ag encounter, CD8+ T cells become activated and begin to proliferate. Early during infection, when Ag-specific effector are proliferating, producing cytokines, lysing infected in vivo, their mitochondrial potential is increased. The purpose of the experiments presented here was determine whether function required for cell function. To block function, transgenic were incubated with increasing doses rotenone, an inhibitor electron transport complex I. Within minutes activation,...

Abstract Studies over the last 100 years have suggested a link between inflammation, infectious disease, and Alzheimer’s Disease (AD). Understanding how immune system changes during development of AD may facilitate new treatments. Here, we studied an aging cohort who had been assessed for pathology with amyloid positron emission tomography cognitive testing, conducted high dimensional flow cytometry on peripheral blood mononuclear cerebrospinal fluid cells. Participants were assigned...

Abstract Suppression of cell-mediated immunity has been proposed as a mechanism that promotes maternal tolerance the fetus but also contributes to increased occurrence and severity certain infections during pregnancy. Despite decades research examining effect pregnancy on Ag-specific T cell responses, many questions remain. In particular, quantitative examination memory CD8 generation following infection remains largely unknown. To examine this issue, we evaluated protective with...

Abstract The manipulation of signals downstream the TCR can have profound consequences for T cell development, function, and homeostasis. Diacylglycerol (DAG) produced after stimulation functions as a secondary messenger mediates signaling to Ras-MEK-Erk NF-κB pathways in cells. DAG kinases (DGKs) convert into phosphatidic acid, resulting termination signaling. In this study, we demonstrate that metabolism by DGKs serve crucial function viral clearance upon lymphocytic choriomeningitis virus...

Previous investigations have defined three upstream activation elements--CCAC, A/T, and TATA sequences--necessary for muscle-specific transcription of the myoglobin gene. In present study, we demonstrate that these sequences elements, prepared as synthetic oligonucleotide cassettes, function synergistically to constitute a cell-type-specific unit. Previously, cognate binding factors recognize CCAC elements were identified. this study determine A/T element binds two nuclear factors, including...

Recent progress in defining molecular components of pathways controlling early stages myogenesis has been substantial, but regulatory factors that govern the striking functional specialization adult skeletal muscle fibers vertebrate organisms have not yet identified. A more detailed understanding temporal and spatial patterns by which specialized fiber characteristics arise may provide dues to identity relevant factors. In this study, we used immunohistochemical, situ hybridization, Northern...

ABSTRACT During many viral infections, antigen-specific CD8 + T cells undergo large-scale expansion. After clearance, the vast majority of effector apoptosis. Previous studies have implicated reactive oxygen intermediates (ROI) in lymphocyte The purpose experiments presented here was to determine role ROI expansion and contraction vivo during a physiological response such as infection. Mice were infected with lymphocytic choriomeningitis virus (LCMV) treated Mn(III)tetrakis(4-benzoic...

Flagellin is a highly effective adjuvant for CD4(+) T cell and humoral immune responses. However, there conflicting data in the literature regarding ability of flagellin to promote CD8(+) response. In this article, we report that immunization wild-type, TLR5(-/-), MyD88(-/-) adoptive transfer recipient mice revealed fusion proteins OVA-specific proliferation independent TLR5 or MyD88 expression by animal. Wild-type TLR5(-/-) APCs were able stimulate high levels vitro response protein...

CD8(+) T cell responses are critical to the control of replication and reactivation associated with gammaherpesvirus infection. Type I interferons (IFNs) have been shown direct indirect roles in supporting development function during viral infection; however, role type latent infection has not examined. Mice deficient IFN signaling (IFNAR1(-/-) mice) high levels murine 68 (MHV68), a model for Epstein-Barr virus. We hypothesized that IFNs enhance anti-gammaherpesvirus response. To test this,...

B cells provide humoral protection against pathogens and promote cellular immunity through diverse nonclassical effector functions. To assess cell function in promoting T homeostasis, mature were either acutely or chronically depleted mice using CD20 mAb. Acute depletion 2- 4-mo-old significantly reduced spleen lymph node CD4(+) CD8(+) numbers, including naive, activated, Foxp3(+)CD25(+)CD4(+) regulatory subsets. The numbers of IFN-γ- TNF-α-producing also reduced. Chronic for 6 mo aged naive...

B ‐cell receptor ( BCR ) ligation generates reactive oxygen intermediates ROI s) that play a role in cellular responses. Although s can oxidize all macromolecules, it was unclear which modifications control In this study, we demonstrate the importance of first oxidation product cysteine, sulfenic acid, and its reversible formation activation. Upon crosslinking, cells increase levels with maximal production occurring within 15 min. Increased ROIs preceded elevated cysteine localized to...