During early viral infection, activation of natural killer (NK) cells elicits the effector functions of target cell lysis and cytokine production. However, the cellular and molecular mechanisms ...leading to NK cell activation during viral infections are incompletely understood. In this study, using a model of acute viral infection, we investigated the mechanisms controlling cytotoxic activity and cytokine production in response to influenza (flu) virus. Analysis of cytokine receptor deficient mice demonstrated that type I interferons (IFNs), but not IL-12 or IL-18, were critical for the NK cell expression of both IFN-γ and granzyme B in response to flu infection. Further, adoptive transfer experiments revealed that NK cell activation was mediated by type I IFNs acting directly on NK cells. Analysis of signal transduction molecules showed that during flu infection, STAT1 activation in NK cells was completely dependent on direct type I IFN signaling, whereas STAT4 activation was only partially dependent. In addition, granzyme B induction in NK cells was mediated by signaling primarily through STAT1, but not STAT4, while IFN-γ production was mediated by signaling through STAT4, but not STAT1. Therefore, our findings demonstrate the importance of direct action of type I IFNs on NK cells to mount effective NK cell responses in the context of flu infection and delineate NK cell signaling pathways responsible for controlling cytotoxic activity and cytokine production.
The goal of this systematic review was to evaluate whether children living in single-parent households have a higher risk of obesity. Of the 539 studies identified using keywords, a total of 10 ...original studies met the inclusion criteria for this review. The outcome measures included objective assessment of adiposity (weight or body mass index (BMI)), dietary consumption, physical activity, and/or obesogenic behaviors (bedroom television, elevated television viewing time, insufficient physical activity, and infrequent family meals). Overall, the studies found higher BMIs and obesogenic behaviors in children of single-parent households. Characteristics identified with this association is comprised of being most prevalent among girls and Black children. Possible explanations for this association include single-parent households having higher time demands due to the lack of shared household responsibilities. Subsequently, a reduction of homemade meals, shared family meals, and physical activity can occur. Also, lower incomes and higher instability related to living transitions may be other possible challenges experienced in single-parent households. Based on the limited number of studies found, further research of the obesity risk in children from single-parent families is recommended. The findings can help provide clinicians and public health programs with a better understanding of how to effectively target family-based interventions for this population.
The role of n-3 polyunsaturated fatty acids (PUFA) on in vivo B-cell immunity is unknown. We first investigated how n-3 PUFAs impacted in vivo B-cell phenotypes and antibody production in the absence ...and presence of antigen compared with a control diet. Lean mice consuming n-3 PUFAs for 4 weeks displayed increased percentage and frequency of splenic transitional 1 B cells. Upon stimulation with trinitrophenylated-lipopolysaccharide, n-3 PUFAs increased the number of splenic transitional 1/2, follicular, premarginal, and marginal zone B cells. n-3 PUFAs also increased surface, but not circulating, IgM. We next tested the effects of n-3 PUFAs in a model of obesity that is associated with suppressed humoral immunity. An obesogenic diet after ten weeks of feeding, relative to a lean control, had no effect on the frequency of B cells but lowered circulating IgM upon antigen stimulation. Administration of n-3 PUFAs to lean and obese mice increased the percentage and/or frequency of transitional 1 and marginal zone B cells. Furthermore, n-3 PUFAs in lean and obese mice increased circulating IgM relative to controls. Altogether, the data show n-3 PUFAs enhance B cell-mediated immunity in vivo, which has implications for immunocompromised populations, such as the obese.
NK cells are a heterogenous population of innate lymphocytes with diverse functional attributes critical for early protection from viral infections. We have previously reported a decrease in ...influenza-induced NK cell cytotoxicity in 6-mo-old C57BL/6 calorically restricted (CR) mice. In the current study, we extend our findings on the influence of CR on NK cell phenotype and function in the absence of infection. We demonstrate that reduced mature NK cell subsets result in increased frequencies of CD127(+) NK cells in CR mice, skewing the function of the total NK cell pool. NK cells from CR mice produced TNF-α and GM-CSF at a higher level, whereas IFN-γ production was impaired following IL-2 plus IL-12 or anti-NK1.1 stimulation. NK cells from CR mice were highly responsive to stimulation with YAC-1 cells such that CD27(-)CD11b(+) NK cells from CR mice produced granzyme B and degranulated at a higher frequency than CD27(-)CD11b(+) NK cells from ad libitum fed mice. CR has been shown to be a potent dietary intervention, yet the mechanisms by which the CR increases life span have yet to be fully understood. To our knowledge, these findings are the first in-depth analysis of the effects of caloric intake on NK cell phenotype and function and provide important implications regarding potential ways in which CR alters NK cell function prior to infection or cancer.
► Aging results in reduced NK cells in the lungs and spleens. ► NK cell function is defective after influenza infection of aged mice. ► A specific defect for interferon-γ production is observed in ...aged NK cells. ► Aged mice have reduced terminally mature NK cells.
Influenza is a public health concern, especially for the elderly. While influenza vaccination is efficacious in the young, it offers only limited protection in the elderly. Thus, it becomes imperative to understand age-related changes in the primary response to influenza infection. This study identified potential age-related defects in natural killer (NK) cell function during influenza infection. We showed that NK cells from aged mice were reduced and had impaired function and altered phenotype in lungs during influenza infection. Aged NK cells demonstrated decreased IFN-γ production, but not degranulation, after influenza infection. However, after ex vivo activation with YAC-1 cells, aged NK cells demonstrated both reduced IFN-γ production and degranulation. IFN-γ was also reduced in aged NK cells after activation with anti-NKp46 and soluble cytokines. IFN-β, and IL-12p40 mRNA expression was not significantly different from that observed in adult mice. Analysis of NK cell subsets indicated that aged mice had more immature and less terminally mature NK cells. These data suggest that aging affects the numbers, function and phenotype of NK cells. Thus, these defects in NK cell function could impair the ability of aged mice to induce a strong antiviral immune response during the early stages of the infection.
Tert-butylhydroquinone (tBHQ) is a commonly used food preservative with known immunomodulatory activity; however, there is little information regarding its role on natural killer (NK) cell activation ...and function. tBHQ is a known activator of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which results in induction of cytoprotective genes. Activation of Nrf2 has been shown to modulate immune responses in a number of different models. In addition, studies in our laboratory have shown that tBHQ inhibits numerous early events following T cell activation. In the current study, we investigated whether activated NK cells are impacted by tBHQ, since many signaling cascades that control NK cell effector function also contribute to T cell function. Splenocytes were isolated from female, wild-type C57Bl/6J mice and treated with 1 μM or 5 μM tBHQ. NK cell function was assessed after activation with phorbol 12-myristate 13-acetate (PMA) and ionomycin for 24 h. Activation of NK cells in the presence of tBHQ decreased total NK cell percentage, production of intracellular interferon gamma (IFNɣ), granzyme B, and perforin, and induction of the cell surface proteins CD25 and CD69, which are markers of NK cell activation. In addition to NK cell effector function, NK cell maturation was also altered in response to tBHQ. Notably, this is the first study to demonstrate that the Nrf2 activator, tBHQ, negatively impacts effector function and maturation of NK cells.
•The synthetic food additive tBHQ modulates NK cell maturation.•TBHQ inhibits induction of the activation markers, CD25 and CD69, in NK cells stimulated with PMA/Ionomycin.•TBHQ inhibits induction of IFNɣ, perforin, and granzyme B in PMA/Ionomycin-stimulated NK cells.
The human gastrointestinal tract is a complex system of digestive pathways aided by mechanical processes, enzymes, transport molecules, and colonic bacteria. Occasionally, these bacterial components ...transplant to atypical locations due to various gastrointestinal imbalances or anatomical structural issues. This may lead to bacterial overgrowth of the small intestine, where minimal or no bacteria are normally found. Symptoms of small intestinal bacterial overgrowth may mimic those of various functional gastrointestinal diseases. Small intestinal bacterial overgrowth is typically diagnosed through hydrogen breath tests or jejunal aspirate culture. Current recommendations indicate antibiotics as the first-line treatment to eradicate or modify the bacterial overgrowth to a more favorable state. Nutritional support is also indicated to correct deficiencies and aid in symptom alleviation. As small intestinal bacterial overgrowth is common in other conditions, much of the research for this area is based on findings in codisease states rather than independent disease research. To provide accurate recommendations for small intestinal bacterial overgrowth, more targeted research is needed.
Vitamin A has been long associated with immune system competence. Vitamin A deficiency is known to compromise many aspects of both innate and adaptive immune responses. Recent advances in retinol ...uptake and metabolism have identified the antigen presenting cell (APC) as a central immune cell capable of vitamin A metabolism. APC are now known to express retinaldehyde dehydrogenase and secrete retinoic acid. The retinoic acid produced has both autocrine and paracrine effects. Autocrine effects include upregulation of CD1d nonclassical major histocompatibility class I-like molecule and matrix metalloproteinase-9. Paracrine effects influence multiple lymphocyte lineage cell populations. Specifically, retinoic acid increases IgA isotype class switching by B lymphocytes, enhances regulatory T cell differentiation, and directs homing of lymphocytes to mucosa. CD1d lipid antigen presentation expands natural killer T cell populations. Previously, the focus of vitamin A action in adaptive immunity was on lymphocytes, but these recent advances suggest the APC may be the central player in carrying out the immune system functions of vitamin A.
•Bone marrow dendritic cell progenitors are reduced in energy restricted mice.•Bone marrow dendritic cell progenitors express reduced levels of CD135.•Bone marrow monocyte and macrophage progenitors ...are increased in energy restricted mice.•Dendritic cell development of energy restricted progenitors can be rescued using common in vitro conditions.
Dendritic cells (DC) are antigen-presenting cells known for stimulating naïve T lymphocytes. The sequential stages of DC development from common myeloid progenitors have been elucidated in murine bone marrow. Energy-restriction (ER) is a pro-longevity dietary intervention with mixed immunological outcomes. The objective of this study was to examine the development of DC in adult C57Bl6J mice fed a 40% ER diet. We observed increased myeloid progenitors, but decreased common DC progenitors, precursor conventional DC and plasmacytoid DC. Furthermore, we observed increased macrophages and cells expressing CD169 in the bone marrow of ER mice. There was no significant difference in DC subsets from unfractionated ER and ad libitum-fed murine bone marrow samples cultured in GM-CSF-supplemented media or Flt3L-supplemented media. Examining rates of proliferation with 6h BrdU incorporation and Ki-67 staining showed these DC progenitor populations have different proliferation rates in ER compared with AL mice. We show here, for the first time, ER results in altered myelopoiesis resulting in reduced DC development but enhanced monocyte/macrophage development in steady-state C57Bl6J mice. In conclusion, these data may partially explain prior observations of impaired early innate immune responses to primary infection such as influenza in ER mice.
Inflammatory bowel diseases (IBD) increase the risk of developing colorectal cancer. Dietary components that reduce inflammation are associated with lower cancer risk. The long-chain omega-3 fatty ...acid docosahexaenoic acid (DHA) is present in fish oil and has potent anti-inflammatory properties. The objective of this study is to determine whether dietary fish oil enriched with DHA (DFO) could reduce experimentally induced colitis and colon cancer risk in a mouse model. When SMAD3-/- mice are exposed to Helicobacter hepaticus, mild colitis is observed 4 weeks postinfection. Mice were fed isocaloric diets modified to include corn oil, safflower oil, or DFO (doses ranging from 0.75% to 6.00%) as the fatty acid source for 8 weeks. Mice were gavaged with H. hepaticus; DFO feeding was continued; and mice were sacrificed 4 weeks after infection. The colon and cecum were collected for histopathology. Spleens and mesenteric lymph nodes were collected and analyzed for T-cell populations using flow cytometry. Contrary to expectations, DFO induced severe colitis and adenocarcinoma formation. DFO consumption was associated with decreased CD8(+) cell frequency and diminished CD69 expression on CD4(+) and CD8(+) T-cell populations. Mice consuming DFO also exhibited higher FoxP3(+) CD25(+) CD4(+) T regulatory cell frequency, FoxP3 expression, and altered L-selectin expression during infection. We concluded that DFO-fed mice may be less equipped to mount a successful response to H. hepaticus infection, increasing colon cancer risk. These results support the need to establish a tolerable upper limit for DHA intake particularly in the context of chronic inflammatory conditions such as IBD.