-
Frontiers in Immunology 2021B-cell receptors, multiple receptor tyrosine kinases, and downstream effectors are constitutively active in chronic lymphocytic leukemia (CLL) B cells. Activation of...
B-cell receptors, multiple receptor tyrosine kinases, and downstream effectors are constitutively active in chronic lymphocytic leukemia (CLL) B cells. Activation of these pathways results in resistance to apoptosis and enhanced survival of the leukemic cells. Idelalisib is a highly selective inhibitor of the PI3K p110∂ isoform and is approved for the treatment of CLL in patients with relapsed/refractory disease or in those harboring 17p deletions or tp53 mutations. Despite the initial excitement centered around high response rates in clinical trials of idelalisib, its therapeutic success has been hindered by the incidence of severe opportunistic infections. To examine the potential contribution of idelalisib to the increased risk of infection, we investigated the effects of idelalisib on the immune cell compartments of healthy donors (HDs) and CLL patients. PI3K∂ blockade by idelalisib reduced the expression levels of inhibitory checkpoint molecules in T cells isolated from both HDs and CLL patients. In addition, the presence of idelalisib in cultures significantly decreased T-cell-mediated cytotoxicity and granzyme B secretion, as well as cytokine secretion levels in both cohorts. Furthermore, idelalisib reduced the proliferation and cytotoxicity of HD NK cells. Collectively, our data demonstrate that both human T and NK cells are highly sensitive to PI3K∂ inhibition. Idelalisib interfered with the functions of T and NK cell cells from both HDs and CLL patients. Therefore, idelalisib might contribute to an increased risk of infections regardless of the underlying B-cell malignancy.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Chromosome Aberrations; Cytokines; Female; Humans; Immune Checkpoint Proteins; Immunocompromised Host; Killer Cells, Natural; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Activation; Male; Middle Aged; Mutation; Phosphoinositide-3 Kinase Inhibitors; Purines; Quinazolinones; T-Lymphocytes
PubMed: 33790890
DOI: 10.3389/fimmu.2021.608625 -
Experimental Gerontology Sep 2021Exercise may attenuate immunosenescence with aging that appears to be accelerated following breast cancer treatment, although limited data on specific cell types exists...
UNLABELLED
Exercise may attenuate immunosenescence with aging that appears to be accelerated following breast cancer treatment, although limited data on specific cell types exists and acute and chronic exercise have been investigated independently in older adults.
PURPOSE
To determine the mucosal associated invariant T (MAIT) cell response to acute exercise before (PRE) and after (POST) 16 weeks of exercise training in breast cancer survivors (BCS) and healthy older women (CON).
METHODS
Age-matched BCS and CON performed 45 min of intermittent cycling at 60% peak power output wattage. Blood samples were obtained at rest, immediately (0 h) and 1 h after exercise to determine MAIT cell counts, frequency, and intracellular cytokine expression.
RESULTS
At PRE, MAIT cell counts were greater in CON (137%) than BCS at 0 h (46%, p < 0.001), with increased MAIT cell frequency in CON but not BCS. TNFα and IFNγ MAIT cell counts increased at 0 h by ~120% in CON (p < 0.001), while BCS counts and frequencies were unchanged. Similar deficits were observed in CD3 and CD3 CD8 cells. At POST, exercise-induced mobilization and egress of MAIT cell counts and frequency showed trends towards improvement in BCS that approached levels in CON. Independent of group, TNFα frequency trended to improve (p = 0.053).
CONCLUSIONS
MAIT mobilization in older BCS following acute exercise was attenuated; however, exercise training may partially rescue these initial deficits, including greater sensitivity to mitogenic stimulation. Using acute exercise before and after interventions provides a unique approach to identify age- and cancer-related immuno-dysfunction that is less apparent at rest.
Topics: Aged; Breast Neoplasms; CD8-Positive T-Lymphocytes; Cancer Survivors; Exercise; Female; Humans; Mucosal-Associated Invariant T Cells
PubMed: 34146655
DOI: 10.1016/j.exger.2021.111454 -
European Journal of Immunology Nov 2016Properly regulated immunity requires precise integration of activating and inhibitory signals. As for other lymphocytes, B cells express an antigen-specific activating...
Properly regulated immunity requires precise integration of activating and inhibitory signals. As for other lymphocytes, B cells express an antigen-specific activating receptor, the B-cell antigen receptor (BCR), and inhibitory receptors (e.g. FcγRIIb) that exercise checkpoint control on B-cell activation. Moreover, following BCR engagement, CD19 recruits proteins that amplify BCR signaling, while CD22 initiates a negative feedback loop by recruiting proteins that inhibit BCR signaling. Initial BCR signaling is mediated by protein tyrosine kinases and lipid kinases; inhibitory receptors directly antagonize the actions of these enzymes by recruiting protein tyrosine phosphatases and lipid phosphatases and positioning them close to actively signaling BCRs. Previously it was thought that inhibitory receptors such as FcγRIIb and CD22 were essential for bringing these phosphatases near the BCR. In this issue of the European Journal of Immunology, Manno et al. show that a tripartite inhibitory module consisting of the adaptor proteins Dok-3 and Grb2 and the lipid phosphatase SHIP1 binds directly to activated BCRs and limits the Ca mobilization that is required for B lymphocyte activation. This reveals that the BCR can be both an activating and inhibitory receptor, one that activates signaling enzymes while initiating a negative feedback loop that prevents excessive signaling.
Topics: B-Lymphocytes; GRB2 Adaptor Protein; Protein Tyrosine Phosphatases; Receptors, Antigen, B-Cell; Signal Transduction
PubMed: 27813071
DOI: 10.1002/eji.201646705 -
Nature Communications Nov 2017Proteasome inhibitors benefit patients with multiple myeloma and B cell-dependent autoimmune disorders but exert toxicity from inhibition of proteasomes in other cells....
Proteasome inhibitors benefit patients with multiple myeloma and B cell-dependent autoimmune disorders but exert toxicity from inhibition of proteasomes in other cells. Toxicity should be minimized by reversible inhibition of the immunoproteasome β5i subunit while sparing the constitutive β5c subunit. Here we report β5i-selective inhibition by asparagine-ethylenediamine (AsnEDA)-based compounds and present the high-resolution cryo-EM structural analysis of the human immunoproteasome. Despite inhibiting noncompetitively, an AsnEDA inhibitor binds the active site. Hydrophobic interactions are accompanied by hydrogen bonding with β5i and β6 subunits. The inhibitors are far more cytotoxic for myeloma and lymphoma cell lines than for hepatocarcinoma or non-activated lymphocytes. They block human B-cell proliferation and promote apoptotic cell death selectively in antibody-secreting B cells, and to a lesser extent in activated human T cells. Reversible, β5i-selective inhibitors may be useful for treatment of diseases involving activated or neoplastic B cells or activated T cells.
Topics: Asparagine; B-Lymphocytes; Binding Sites; Cell Line, Tumor; Cryoelectron Microscopy; Humans; Lymphocyte Activation; Lymphocytes; Models, Molecular; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Subunits; Static Electricity; T-Lymphocytes
PubMed: 29167449
DOI: 10.1038/s41467-017-01760-5 -
Oncotarget Jun 2016As a master metabolic sensor, AMP-activated protein kinase (AMPK) is involved in different fundamental cellular processes. Regulation of AMPK activity either by agonists...
As a master metabolic sensor, AMP-activated protein kinase (AMPK) is involved in different fundamental cellular processes. Regulation of AMPK activity either by agonists (e.g., AICAR) or by antagonists (e.g., Compound C) has been widely employed to study the physiological functions of AMPK. However, mounting evidence indicates AMPK-independent effects for these chemicals and how they regulate immune cell functions remains largely unknown. Herein, using T cells from AMPK conditional knockout mice and their wild type littermates, we demonstrate that AICAR and Compound C can, indeed, activate or inhibit AMPK activity in T cells, respectively. Specifically, AICAR inhibits, but Compound C promotes, Ca2+-induced T cell death in an AMPK-dependent manner. In contrast, our data also demonstrate that AICAR and Compound C inhibit T cell activation and cytokine production in an AMPK-independent manner. Moreover, we find that the AMPK-independent activity of AICAR and Compound Cis mediated via the mTOR signaling pathway in activated T cells. Our results not only reveal the critical role of AMPK in regulating T cell survival and function, but also demonstrate AMPK-dependent and independent rolesof AICAR/Compound C in regulating T cell responses, thus suggesting a context-dependent effect of these "AMPK regulators".
Topics: AMP-Activated Protein Kinases; Aminoimidazole Carboxamide; Animals; Calcium Signaling; Cell Death; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Activators; Genotype; Immunologic Factors; Lymphocyte Activation; Mice, Knockout; Phenotype; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Ribonucleosides; T-Lymphocytes; TOR Serine-Threonine Kinases
PubMed: 27177226
DOI: 10.18632/oncotarget.9277 -
Proceedings of the National Academy of... Jul 1997We report that human immunodeficiency virus type 1 (HIV-1) has evolved a self-perpetuating mechanism to actively generate cells permissive for productive and cytopathic...
We report that human immunodeficiency virus type 1 (HIV-1) has evolved a self-perpetuating mechanism to actively generate cells permissive for productive and cytopathic infection. Only activated T cells can be productively infected, which leads to their rapid depletion (2 x 10(9)/day in an infected individual). Establishment of productive HIV-1 infection therefore requires continual activations from the large pool of quiescent T cells. Tat protein, which is secreted by infected cells, activated uninfected quiescent T cells in vitro and in vivo. These Tat-activated uninfected cells became highly permissive for productive HIV-1 infection. Activation of primary T cells by Tat protein involved integrin receptors and was associated with activation of mitogen-activated protein kinases, including ERK1 and JNK kinase. Accordingly, these primary T cells progressed from G0 to the late G1 phase of the cell cycle.
Topics: Calcium-Calmodulin-Dependent Protein Kinases; Carrier Proteins; Cells, Cultured; Enzyme Activation; Gene Products, tat; HIV Infections; HIV-1; Humans; Integrins; Jurkat Cells; Lymphocyte Activation; T-Lymphocytes; Virus Replication; tat Gene Products, Human Immunodeficiency Virus
PubMed: 9223324
DOI: 10.1073/pnas.94.15.8116 -
Nucleic Acids Research Nov 2020Although endogenous retroviruses (ERVs) are known to harbor cis-regulatory elements, their role in modulating cellular immune responses remains poorly understood. Using...
Although endogenous retroviruses (ERVs) are known to harbor cis-regulatory elements, their role in modulating cellular immune responses remains poorly understood. Using an RNA-seq approach, we show that several members of the ERV9 lineage, particularly LTR12C elements, are activated upon HIV-1 infection of primary CD4+ T cells. Intriguingly, HIV-1-induced ERVs harboring transcription start sites are primarily found in the vicinity of immunity genes. For example, HIV-1 infection activates LTR12C elements upstream of the interferon-inducible genes GBP2 and GBP5 that encode for broad-spectrum antiviral factors. Reporter assays demonstrated that these LTR12C elements drive gene expression in primary CD4+ T cells. In line with this, HIV-1 infection triggered the expression of a unique GBP2 transcript variant by activating a cryptic transcription start site within LTR12C. Furthermore, stimulation with HIV-1-induced cytokines increased GBP2 and GBP5 expression in human cells, but not in macaque cells that naturally lack the GBP5 gene and the LTR12C element upstream of GBP2. Finally, our findings suggest that GBP2 and GBP5 have already been active against ancient viral pathogens as they suppress the maturation of the extinct retrovirus HERV-K (HML-2). In summary, our findings uncover how human cells can exploit remnants of once-infectious retroviruses to regulate antiviral gene expression.
Topics: Animals; CD4-Positive T-Lymphocytes; Endogenous Retroviruses; GTP-Binding Proteins; Gene Expression Regulation; HEK293 Cells; HIV Infections; HIV-1; Humans; Macaca mulatta; Promoter Regions, Genetic; T-Lymphocyte Subsets
PubMed: 33021676
DOI: 10.1093/nar/gkaa832 -
International Journal of Molecular... Jun 2019Several studies indicate that acute exercise induces DNA damage, whereas regular exercise increases DNA repair kinetics. Although the molecular mechanisms are not...
Several studies indicate that acute exercise induces DNA damage, whereas regular exercise increases DNA repair kinetics. Although the molecular mechanisms are not completely understood, the induction of endogenous reactive oxygen species (ROS) during acute exhaustive exercise due to metabolic processes might be responsible for the observed DNA damage, while an adaptive increase in antioxidant capacity due to regular physical activity seems to play an important protective role. However, the protective effect of physical activity on exogenously induced DNA damage in human immune cells has been poorly investigated. We asked the question whether individuals with a high aerobic capacity would have an enhanced response to radiation-induced DNA damage. Immune cells are highly sensitive to radiation and exercise affects lymphocyte dynamics and immune function. Therefore, we measured endogenous and radiation-induced DNA strand breaks and poly (ADP-ribose) polymerase-1 (PARP1) activity in peripheral blood mononuclear cells (PBMCs) from endurance-trained (maximum rate of oxygen consumption measured during incremental exercise V'O > 55 mL/min/kg) and untrained (V'O < 45 mL/min/kg) young healthy male volunteers before and after exhaustive exercise. Our results indicate that: (i) acute exercise induces DNA strand breaks in lymphocytes only in untrained individuals, (ii) following acute exercise, trained individuals repaired radiation-induced DNA strand breaks faster than untrained individuals, and (iii) trained subjects retained a higher level of radiation-induced PARP1 activity after acute exercise. The results of the present study indicate that increased aerobic fitness can protect immune cells against radiation-induced DNA strand breaks.
Topics: DNA Damage; DNA Repair; Exercise; Humans; Leukocytes, Mononuclear; Lymphocytes; Physical Fitness; Poly (ADP-Ribose) Polymerase-1; Radiation, Ionizing
PubMed: 31248182
DOI: 10.3390/ijms20122999 -
Autophagy Feb 2020Obesity is associated with changes in the immune system that significantly hinder its ability to mount efficient immune responses. Previous studies have reported a...
Obesity is associated with changes in the immune system that significantly hinder its ability to mount efficient immune responses. Previous studies have reported a dysregulation of immune responses caused by lipid challenge; however, the mechanisms underlying that dysregulation are still not completely understood. Autophagy is an essential catabolic process through which cellular components are degraded by the lysosomal machinery. In T cells, autophagy is an actively regulated process necessary to sustain homeostasis and activation. Here, we report that CD4 T cell responses are inhibited when cells are challenged with increasing concentrations of fatty acids. Furthermore, analysis of T cells from diet-induced obese mice confirms that high lipid load inhibits activation-induced responses in T cells. We have found that autophagy is inhibited in CD4 T cells exposed or to lipid stress, which causes decreased autophagosome formation and degradation. Supporting that inhibition of autophagy caused by high lipid load is a key mechanism that accounts for the effects on T cell function of lipid stress, we found that ATG7 (autophagy-related 7)-deficient T cells, unable to activate autophagy, did not show additional inhibitory effects on their responses to activation when subjected to lipid challenge. Our results indicate, thus, that increased lipid load can dysregulate autophagy and cause defective T cell responses, and suggest that inhibition of autophagy may underlie some of the characteristic obesity-associated defects in the T cell compartment.: ACTB: actin, beta; ATG: autophagy-related; CDKN1B: cyclin-dependent kinase inhibitor 1B; HFD: high-fat diet; IFNG: interferon gamma; IL: interleukin; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPK3/ERK1: mitogen-activated protein kinase 3; MAPK8/JNK: mitogen-activated protein kinase 8; LC3-I: non-conjugated form of MAP1LC3B; LC3-II: phosphatidylethanolamine-conjugated form of MAP1LC3B; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MS: mass spectrometry; MTOR: mechanistic target of rapamycin kinase; NFATC2: nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2; NLRP3: NLR family, pyrin domain containing 3; OA: oleic acid; PI: propidium iodide; ROS: reactive oxygen species; STAT5A: signal transducer and activator of transcription 5A; TCR: T cell receptor; T1: T helper cell type 1.
Topics: Animals; Autophagy; CD4-Positive T-Lymphocytes; Cell Proliferation; Cytokines; Diet, High-Fat; Down-Regulation; Female; Homeostasis; Humans; Lipids; Lymphocyte Activation; Mice, Inbred C57BL; Obesity; Oleic Acid; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 30982401
DOI: 10.1080/15548627.2019.1606635 -
Arthritis Research & Therapy 2006The efficiency of activating latent transforming growth factor (TGF)-beta1 in systemic lupus erythematosus (SLE) may control the balance between inflammation and... (Comparative Study)
Comparative Study
The efficiency of activating latent transforming growth factor (TGF)-beta1 in systemic lupus erythematosus (SLE) may control the balance between inflammation and fibrosis, modulating the disease phenotype. To test this hypothesis we studied the ability to activate TGF-beta1 in SLE patients and control individuals within the context of inflammatory disease activity, cumulative organ damage and early atherosclerosis. An Activation Index (AI) for TGF-beta1 was determined for 32 patients with SLE and 33 age-matched and sex-matched control individuals by quantifying the increase in active TGF-beta1 under controlled standard conditions. Apoptosis in peripheral blood mononuclear cells was determined by fluorescence-activated cell sorting. Carotid artery intima-media thickness was measured using standard Doppler ultrasound. These measures were compared between patients and control individuals. In an analysis conducted in patients, we assessed the associations of these measures with SLE phenotype, including early atherosclerosis. Both intima-media thickness and TGF-beta1 AI for SLE patients were within the normal range. There was a significant inverse association between TGF-beta1 AI and levels of apoptosis in peripheral blood mononuclear cells after 24 hours in culture for both SLE patients and control individuals. Only in SLE patients was there a significant negative correlation between TGF-beta1 AI and low-density lipoprotein cholesterol (r = -0.404; P = 0.022) and between TGF-beta1 AI and carotid artery intima-media thickness (r = -0.587; P = 0.0004). A low AI was associated with irreversible damage (SLICC [Systemic Lupus International Collaborating Clinics] Damage Index > or = 1) and was inversely correlated with disease duration. Intima-media thickness was significantly linked to total cholesterol (r = 0.371; P = 0.037). To conclude, in SLE low normal TGF-beta1 activation was linked with increased lymphocyte apoptosis, irreversible organ damage, disease duration, calculated low-density lipoprotein levels and increased carotid IMT, and may contribute to the development of early atherosclerosis.
Topics: Apoptosis; Atherosclerosis; Cholesterol, LDL; England; Female; Humans; Lupus Erythematosus, Systemic; Lymphocytes; Male; Reference Values; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tunica Media; White People
PubMed: 16646981
DOI: 10.1186/ar1951