Background & Aims Intraepithelial T lymphocyte cells (IEL) are the first immune cells to respond to pathogens; they help maintain the integrity of the epithelial barrier. We studied the function of ...the mouse glycoprotein Signaling Lymphocyte Activation Molecule Family receptor (SLAMF) 4 (encoded by Slamf4 ) on the surface of CD8αβ αβ T-cell receptor (TCR)+ IELs, and the roles of these cells in homeostasis of the small intestine in mice. Methods SLAMF4− CD8+ αβTCR+ cells isolated from spleens of OT-I Rag1−/− mice were induced to express gut-homing receptors and transferred to C57BL/6J mice; levels of SLAMF4+ cells were measured in small intestine tissues. After administration of anti-CD3 or antigen, with or without anti-SLAM4, to C57BL/6J and Slamf4−/− mice, CD8αβ αβTCR+ IELs were collected; cytokine production and cytotoxicity were measured. Depletion of CX3CR1+ phagocytes was assessed in mice by live-cell confocal imaging or by cytofluorometry; small intestine tissues were analyzed by histology and inflammation was quantified. Results Splenic CD8+ αβTCR+ cells began to express SLAMF4 only after migrating to the small intestine. Injection of C57BL/6J mice with anti-SLAMF4 and anti-CD3 increased levels of interleukin 10 and interferon gamma secretion by IEL, compared with injection of anti-CD3 only. Similarly, the number of granzyme B+ cytotoxic CD8+ αβTCR+ IELs increased in Slamf4−/− mice after injection of anti-CD3 and anti-SLAMF4, administration of antigen, or injection of anti-CD3. Surprisingly, in vivo activation of CD8αβ+ IELs with anti-CD3 or antigen caused transient depletion of CX3CR1+ phagocytes, which was prolonged by co-injection with anti-SLAMF4 or in Slamf4−/− mice. Anti-CD3 aggravated inflammation in the small intestines of Slamf4−/− mice and Eat2a−/− Eat2b−/− mice, indicated by flattened villi and crypt hyperplasia. Conclusions In mice, the intestinal environment induces SLAMF4 expression and localization to the surface of CD8+ αβTCR+ IELs. Signaling via SLAMF4 controls expansion of cytotoxic CD8αβ+ IELs, which regulate the reversible depletion of lamina propria phagocytes and inflammation in the small intestine.
Background & Aims Signaling lymphocyte activation molecule (Slamf)1 is a co-stimulatory receptor on T cells and regulates cytokine production by macrophages and dendritic cells. Slamf1 regulates ...microbicidal mechanisms in macrophages, therefore we investigated whether the receptor affects development of colitis in mice. Methods We transferred CD45RBhi CD4+ T cells into Rag−/− or Slamf1−/− Rag−/− mice to induce colitis. We also induced colitis by injecting mice with an antibody that activates CD40. We determined the severity of enterocolitis based on disease activity index, histology scores, and levels of cytokine production, and assessed the effects of antibodies against Slamf1 on colitis induction. We quantified migration of monocytes and macrophage to inflamed tissues upon induction of colitis or thioglycollate-induced peritonitis and in response to tumor necrosis factor-α in an air-pouch model of leukocyte migration. Results Colitis was reduced in Slamf1−/− Rag−/− mice, compared with Rag−/− mice, after transfer of CD45RBhi CD4+ T cells or administration of the CD40 agonist. The numbers of monocytes and macrophages were reduced in inflamed tissues of Slamf1−/− Rag−/− mice, compared with Rag−/− mice, after induction of colitis and other inflammatory disorders. An antibody that inhibited Slamf1 reduced the level of enterocolitis in Rag−/− mice. Conclusions Slamf1 contributes to the development of colitis in mice. It appears to indirectly regulate the appearance of monocytes and macrophages in inflamed intestinal tissues. Antibodies that inhibit Slamf1 reduce colitis in mice, so human SLAMF1 might be a therapeutic target for inflammatory bowel disease.
Abstract
Slamf8 (CD353) is a novel cell surface receptor that is expressed upon activation of resident peritoneal macrophages by interferon-gamma or bacteria. In studying innate immune responses of ...Slamf8-/- macrophages and dendritic cells, we found a very high activity of the Nox2 enzyme, not only in response to E.coli or S.aureus, but also to phorbol myristate acetate. Thus, Slamf8 acts as a negative regulator of Nox2 activity, which was confirmed by a reduction of the enzyme activity after transfection of the receptor into Slamf8-deficient primary or RAW 264.7 macrophages. The elevated Nox2 activity in Slamf8-/- macrophages partially reverted lowering of the pH in E.coli or S.aureus phagosomes. Consequently, in Slamf8-/- macrophages and dendritic cells MHC Class II antigen presentation to CD4 T+ cells is dramatically increased compared to wt cells. Taken together, the data show that upon response to inflammation-associated stimuli the inducible receptor Slamf8 negatively regulates antigen presentation.
The induced polarization characteristics of oil-bearing rocks in reservoirs can play a key role in reservoir evaluation in the stage of oil and gas exploration and development. With the continuous ...advancement of oil and gas exploration, low porosity and low permeability reservoirs have become important objects of exploration and development, but the research on the response mechanism of complex resistivity of reservoir rocks is still not deep enough. In this study, the reservoir rocks with low porosity and low permeability were taken as the research object. By measuring the complex resistivity of oil-bearing rock samples under two different wetting conditions, the amplitude and phase of complex resistivity of reservoir rocks under different oil saturation were obtained. The MGEMTIP model was used to invert the low-frequency data and calculate IP parameters such as DC resistivity and polarizability to study the induced polarization characteristics of reservoir rocks under different oil saturation conditions. The results showed that the DC resistivity of reservoir rocks increased with the increase of oil saturation, and the trend was influenced by the conductivity of oil-water mixture and rock surface. When the oil saturation was about 45%, for the same rock, with the increase of contact angle before and after aging, the DC resistivity had a certain downward trend. Under low oil saturation, the polarizability of relatively hydrophilic rocks tended to increase with the increase of oil saturation. After the wettability was changed, the reservoir rocks were relatively hydrophobic, and the polarizability first decreased with the increase of oil saturation, and then under the influence of Maxwell-Wagner polarization, the polarizability of the rocks increased with the increase of oil saturation. Therefore, the characteristics of induced polarization of reservoirs with different wettability can provide physical basis for oil reservoir exploration, development and evaluation.
•The samples are low porosity and low permeability reservoir rocks.•Analyze the influence mechanism of wettability on IP characteristics.•Inverse IP parameters by MGEMTIP model.•Change the wettability of crude oil.•Establish relationship between IP parameters and wettability.
Abstract
SLAMF4 is a cell surface receptor, which is primarily known as a regulator of cytotoxicity and cytokine secretion by mouse NK cells upon engagement with its counter-structure CD48. Here, we ...found SLAMF4 is highly expressed on the surface of most mucosal CD8+ T cells, whereas it is only expressed on some CD44+ CD8+ splenic cells. Upon transfer of naïve SLAMF4− CD8+ T cells derived from Thy1.2+ B6 mice into Thy1.2− B6, donor cells were found to express SLAMF4 after entry into the mucosa. The increase in SLAMF4+ CD8+ cells was due to upregulation of the receptor gene rather than to expansion of a small subset of memory CD8+ T cells. Consistent with the high level of IL-15 in the intestinal mucosa and its requirement for the maintenance of memory CD8+ T cells, we found that recombinant IL-15 induces SLAMF4, particularly the short isoform of SLAMF4, expression on CD8+ T cells. Costimulation with αSLAMF4 significantly increased the αCD3ϵ-induced infiltration of CD8+ T cells in small intestine and exacerbated the inflammation in the small intestine of IL-10-IRES-GFP reporter mouse. As control, αSLAMF4 alone did not cause inflammation in the intestine. In conclusion, the differential expression on mucosal CD8+ T cells as well as the dual nature of SLAMF4 function suggests that SLAMF4 might be involved in regulating the fine balance between the maintenance of tolerance and immune surveillance in the intestinal mucosa.
Slamf8 (CD353) is a cell surface receptor that is expressed upon activation of macrophages by interferon-gamma or bacteria. Here we report that a very high Nox2 activity enzyme was found in
Slamf8
...−/− macrophages in response to
E.coli
or
S.aureus
, but also to phorbol myristate acetate. The elevated Nox2 activity in
Slamf8
−/− macrophages was also demonstrated in
E.coli
or
S.aureus
phagosomes by using a pH indicator system, and was further confirmed by a reduction of the enzyme activity after transfection of the receptor into Slamf8-deficient primary macrophages or RAW 264.7 cells. Upon exposure to bacteria and/or phorbol myristate acetate, PKC activity in
Slamf8
−/− macrophages is increased. This results in an enhanced phosphorylation of p40phox, one key component of the Nox2 enzyme complex, which in turn leads to greater Nox2 activity. Taken together, the data show that upon response to inflammation-associated stimuli the inducible receptor Slamf8 negatively regulates inflammatory responses.
Abstract
Signaling lymphocyte activation molecule (Slamf1) is a T cell co-stimulatory molecule and a regulator of cytokine production by macrophages and dendritic cells. Because Slamf1 positively ...regulates microbicidal mechanisms in macrophages, we evaluate whether Slamf1 would affect enterocolitis. To induce colitis, mouse CD45RBhi CD4+ T cells were transferred into RAG-/- or Slamf1-/- RAG-/- recipient mice. In a second set of experiments, an agonistic αCD40 antibody was administered to the same recipient strains to induce colitis. Whilst the absence of Slamf1 in RAG-/- recipients mitigated colitis, the function of disease-causing effector or regulatory T cells was not affected by the ablation of the receptor. Surprisingly, in Slamf1-/- mice monocyte / macrophage migration into the inflamed tissue was impaired not only in αCD40-induced colitis but also in two other in vivo models of inflammation: thioglycolate induced peritonitis and in an “air pouch” model in response to TNFα. Administering αSlamf1 to RAG-/- mice ameliorated enterocolitis and altered this migration. Slamf1 is a key contributor to the innate immune responses during experimental colitis by affecting the migration of monocytes / macrophages to the sites of inflammation. As αSlamf1 also mitigates the pathogenesis of colitis, SLAMF1 should be a plausible therapeutic target in treating inflammatory bowel diseases.
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