National Academy of Sciences
Immunology
199.3K views |
+19 today
Teaching and Learning Immunology. Information you never would have searched for!
Curated by
Gilbert C FAURE
 Your new post is loading...
Your new post is loading...
Scoop.it!
The transporter associated with antigen processing (TAP) selectively translocates antigenic peptides into the endoplasmic reticulum. Loading onto MHC class I molecules and proofreading of these bound epitopes are orchestrated within the macromolecular peptide-loading complex, which assembles on TAP. This heterodimeric ABC-binding cassette (ABC) transport complex is therefore a major component in the adaptive immune response against virally or malignantly transformed cells. Its pivotal role predestines TAP as a target for infectious diseases and malignant disorders. The development of therapies or drugs requires a detailed comprehension of structure and function of this ABC transporter, but our knowledge about various aspects is still insufficient. This review highlights recent achievements on the structure and dynamics of antigenic peptides in complex with TAP. Understanding the binding mode of antigenic peptides in the TAP complex will crucially impact rational design of inhibitors, drug development, or vaccination strategies. 
Scoop.it!
Highlights •Leukocytes generate micron-scale gaps when squeezing through inflamed vessels •Gap formation by squeezing leukocytes does not require endothelial contractility •Transmigrating T cells deform and insert nuclear lobes into their lamellipodia •These lobes bend endothelial stress fibers and disassemble the thinner actin filaments
Via Krishan Maggon
Scoop.it!
Mechanisms that govern PD1 expression and exhaustion in T cells are not fully understood. In this issue of Immunity, Stephen et al. (2017) uncover a key role for the genome organizer Satb1 in restraining PD1 expression and promoting tumor immunity.
Via Krishan Maggon
Krishan Maggon 's curator insight,
January 26, 2017 3:35 AM
Satb1: Restraining PD1 and T Cell Exhaustion
Briana G. Nixon, Ming O. Li Immunity Volume 46, Issue 1, p3–5, 17 January 2017
Scoop.it!
The green pus you see if a wound is infected is gross, but it’s also a sign that the immune system has things under control. An enzyme called
Gilbert C FAURE's insight:
MPO inside
Scoop.it!
Author Summary During infection, pathogens must overcome the restriction of essential nutrients such as manganese by the host, while simultaneously coping with other host defenses such as the oxidative burst. Using the host protein that limits manganese availability during infection and mice lacking this effector, we determined that acquisition of a second superoxide dismutase that is capable of using either manganese or iron enhances the ability of Staphylococcus aureus to cause infection. When manganese-starved by the host, this cambialistic enzyme enables S. aureus to maintain superoxide dismutase activity and survive when exposed to oxidative stress. These results reveal the important contribution of cambialistic superoxide dismutases to bacterial pathogenesis and represent a new mechanism for resisting manganese starvation during infection.
Scoop.it!
Epigenetic mechanisms play a critical role during differentiation of T cells by contributing to the formation of stable and heritable transcriptional patterns. To better understand the mechanisms of memory maintenance in CD8+ T cells, we performed genome-wide analysis of DNA methylation, histone marking (acetylated lysine 9 in histone H3 and trimethylated lysine 9 in histone), and gene-expression profiles in naive, effector memory (EM), and terminally differentiated EM (TEMRA) cells. Our results indicate that DNA demethylation and histone acetylation are coordinated to generate the transcriptional program associated with memory cells. Conversely, EM and TEMRA cells share a very similar epigenetic landscape. Nonetheless, the TEMRA transcriptional program predicts an innate immunity phenotype associated with genes never reported in these cells, including several mediators of NK cell activation ( VAV3 and LYN ) and a large array of NK receptors (e.g., KIR2DL3 , KIR2DL4 , KIR2DL1 , KIR3DL1 , KIR2DS5 ). In addition, we identified up to 161 genes that encode transcriptional regulators, some of unknown function in CD8+ T cells, and that were differentially expressed in the course of differentiation. Overall, these results provide new insights into the regulatory networks involved in memory CD8+ T cell maintenance and T cell terminal differentiation.
Scoop.it!
Natural killer (NK) cells are characterized by their ability to detect and induce apoptosis of susceptible target cells and by the secretion of immunoregulatory cytokines such as IFN-gamma. The activation of these effector functions is triggered upon recognition of tumor and pathogen (mostly virus)-infected cells and as a consequence of a bidirectional crosstalk that NK cells establish with other cells of myeloid origin such as dendritic cells (DC) and macrophages. A common characteristic of these myeloid cells is their ability to secrete different members of the IL-12 family of cytokines such as IL-12, IL-23 and IL-27, and cytokines such as IL-15 and IL-18. Although the effect of IL-12, IL-15 and IL-18 has been characterized, the effect of IL-23 and IL-27 on NK cells (especially human), remains ill-defined. Particularly, IL-27 is a cytokine with dual functions as it has been described as pro- and as anti-inflammatory in different experimental settings. However, recent evidence indicates that this cytokine indeed promotes human NK cell activation, IFN- secretion, NKp46-dependent NK cell-mediated cytotoxicity and antibody (Ab)-dependent NK cell-mediated cytotoxicity (ADCC) against monoclonal Ab (mAb)-coated tumor cells. Remarkably, IL-27 also primes NK cells for IL-18 responsiveness, enhancing these functional responses. Consequently, IL-27 acts as a pro-inflammatory cytokine that, in concert with other DC-derived cytokines, hierarchically contributes to NK cells activation and effector functions, which likely contributes to foster the adaptive immune response in different physiopathological conditions.
Scoop.it!
Signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) mutations in X-linked lymphoproliferative disease (XLP) lead to defective NKT cell development and impaired humoral immunity. Because of the redundancy of SLAM family receptors (SFRs) and the complexity of SAP actions, how SFRs and SAP mediate these processes remains elusive. Here, we examined NKT cell development and humoral immunity in mice completely deficient in SFR. We found that SFR deficiency severely impaired NKT cell development. In contrast to SAP deficiency, SFR deficiency caused no apparent defect in follicular helper T (TFH) cell differentiation. Intriguingly, the deletion of SFRs completely rescued the severe defect in TFH cell generation caused by SAP deficiency, whereas SFR deletion had a minimal effect on the defective NKT cell development in SAP-deficient mice. These findings suggest that SAP-dependent activating SFR signaling is essential for NKT cell selection; however, SFR signaling is inhibitory in SAP-deficient TFH cells. Thus, our current study revises our understanding of the mechanisms underlying T cell defects in patients with XLP.
Scoop.it!
Immunotherapeutic antibodies are a promising cancer therapy, but little is known about the nontargeted effects of these antibodies on immune cells through Fc receptor binding. Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs), which have been implicated in both promoting and inhibiting tumor growth, express abundant Fcγ receptors. Lehmann et al . examined these cells in tumors growing in different sites—skin and lung. They found that the organ environment in which a tumor grows determined which TAM and TAN subpopulations contributed to antibody-dependent tumor immunotherapy. Different cellular pathways underlay the antibody response in different tissues. These data may help fine-tune therapeutic strategies to target cells that promote tumors and not those that fight them. Via Krishan Maggon
Gilbert C FAURE's insight:
local immunology at last
Krishan Maggon 's curator insight,
January 20, 2017 3:36 AM
Science Immunology 06 Jan 2017: Vol. 2, Issue 7, DOI: 10.1126/sciimmunol.aah6413
Scoop.it!
Classically viewed as homogeneous effector cells with poor regulatory functions, neutrophils
|
Scoop.it!
Welcome to the official website of the 17th International HLA and Immunogenetics Workshop (IHIWS), scheduled for September 6–10, 2017 in Pacific Grove, CA.
Scoop.it!
Cell. 2016 Oct 6;167(2):433-443.e14. doi: 10.1016/j.cell.2016.08.072. Epub 2016 Sep 22. Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Scoop.it!
CD4+ T helper cells are a valuable component of the immune response towards cancer. Unfortunately, natural tumour‐specific CD4+ T cells occur in low frequency, express relatively low‐affinity T cel
Scoop.it!
NKT cells recognize lipid Ags presented by a class I MHC-like molecule CD1d, a member of the CD1 family. Although most initial studies on NKT cells focused on a subset with semi-invariant TCR termed invariant NKT cells, the majority of CD1d-restricted lipid-reactive human T cells express diverse TCRs and are termed type II NKT cells. These cells constitute a distinct population of circulating and tissue-resident effector T cells with immune-regulatory properties. They react to a growing list of self- as well as non–self-lipid ligands, and share some properties with both invariant NKT and conventional T cells. An emerging body of evidence points to their role in the regulation of immunity to pathogens/tumors and in autoimmune/metabolic disorders. An improved understanding of the biology of these cells and the ability to manipulate their function may be of therapeutic benefit in diverse disease conditions.
Scoop.it!
Frontiers | STATs in NK-Cells: The Good, the Bad, and the Ugly | NK and Innate Lymphoid Cell Biology
NK-cells are major players in the fight against viral infections and transformed cells, but there is increasing evidence attributing a disease-promoting role to NK-cells. Cytokines present in the tumor microenvironment shape NK-cell maturation, function and effector responses. Many cytokines signal via the JAK-STAT pathway that is also frequently altered and constitutively active in a broad range of tumor cells. As a consequence, there are currently major efforts to develop therapeutic strategies to target this pathway. It is therefore of utmost importance to understand the role and contributions of JAK-STAT molecules in NK-cell biology - only this knowledge will allow us to predict effects of JAK-STAT inhibition for NK-cell functions and to successfully apply precision medicine. We will review the current knowledge on the role of JAK-STAT signaling for NK-cell functions and discuss conditions involved in the switch from NK-cell tumor surveillance to disease promotion.
Scoop.it!
Dendritic cells are targeted by regulatory T (T reg) cells, in a manner that operates as an indirect mode of T cell suppression. In this study, using a combination of single-cell force spectroscopy and structured illumination microscopy, we analyze individual T reg cell–DC interaction events and show that T reg cells exhibit strong intrinsic adhesiveness to DCs. This increased DC adhesion reduces the ability of contacted DCs to engage other antigen-specific cells. We show that this unusually strong LFA-1–dependent adhesiveness of T reg cells is caused in part by their low calpain activities, which normally release integrin–cytoskeleton linkage, and thereby reduce adhesion. Super resolution imaging reveals that such T reg cell adhesion causes sequestration of Fascin-1, an actin-bundling protein essential for immunological synapse formation, and skews Fascin-1–dependent actin polarization in DCs toward the T reg cell adhesion zone. Although it is reversible upon T reg cell disengagement, this sequestration of essential cytoskeletal components causes a lethargic state of DCs, leading to reduced T cell priming. Our results reveal a dynamic cytoskeletal component underlying T reg cell–mediated DC suppression in a contact-dependent manner.
Scoop.it!
Highlights • IL-17A (IL-17) is produced by multiple cell subsets, including CD8+ T cells. • The presence of IL-17+ CD8+ T cells in human inflammatory diseases suggests these cells may contribute to immunopathology. • Increased knowledge of human IL-17+ CD8+ T cells will enhance our overall understanding of their role in human disease.
Gilbert C FAURE's insight:
Immunology Letters Volume 178, October 2016, Pages 20–26 ECI 2015 Cover image IL-17+ CD8+ T cells: Differentiation, phenotype and role in inflammatory disease Ushani Srenathan1, Kathryn Steel1, Leonie S. Taams, 1, Show more http://dx.doi.org/10.1016/j.imlet.2016.05.001
Scoop.it!
CD33-related Siglecs are a family of proteins widely expressed on innate immune cells. Binding of sialylated glycans or other ligands triggers signals that inhibit or activate inflammation. Immunomodulation by Siglecs has been extensively studied, but relationships between structure and functions are poorly explored. Here we present new data relating to the structure and function of Siglec-E, the major CD33-related Siglec expressed on mouse neutrophils, monocytes, macrophages, and dendritic cells. We generated nine new rat monoclonal antibodies specific to mouse Siglec-E, with no cross-reactivity to Siglec-F. Although all antibodies detected Siglec-E on transfected human HEK-293T cells, only two reacted with mouse bone marrow neutrophils by flow cytometry and on spleen sections by immunohistochemistry. Moreover, whereas all antibodies recognized Siglec-E-Fc on immunoblots, binding was dependent on intact disulfide bonds and N-glycans, and only two antibodies recognized native Siglec-E within spleen lysates. Thus, we further investigated the impact of Siglec-E homodimerization. Homology-based structural modeling predicted a cysteine residue (Cys-298) in position to form a disulfide bridge between two Siglec-E polypeptides. Mutagenesis of Cys-298 confirmed its role in dimerization. In keeping with the high level of 9-O-acetylation found in mice, sialoglycan array studies indicate that this modification has complex effects on recognition by Siglec-E, in relationship to the underlying structures. However, we found no differences in phosphorylation or SHP-1 recruitment between dimeric and monomeric Siglec-E expressed on HEK293A cells. Phylogenomic analyses predicted that only some human and mouse Siglecs form disulfide-linked dimers. Notably, Siglec-9, the functionally equivalent human paralog of Siglec-E, occurs as a monomer.
Scoop.it!
Continuous production of blood cells unfolds within a complex three-dimensional tissue scaffold established by highly organized stromal cell networks of mesenchymal, neural and vascular origin inside bone marrow cavities. Collectively, stromal cells have been shown to serve two principal roles; first as primary participants of bone remodeling and metabolism, second as master regulators of different stages of blood cell development and production. Indeed, ample evidence demonstrates that stromal cells can sense and integrate systemic signals to shape hematopoietic responses, and that these regulatory mechanisms are subverted in multiple pathologic conditions. Microbial infections are stressors that elicit potent inflammatory reactions and induce substantial alterations of hematopoietic output. Whether the cellular components of the BM stromal microenvironment are targeted by infections and participate in infection-induced hematopoiesis has not been investigated in sufficient detail to date. In this manuscript we provide a succinct updated overview of the different cell populations that are currently known to form BM stroma. We discuss experimental evidence demonstrating that different stromal components are actively damaged or functionally altered by pathogens and/or ensuing inflammatory signals, and review how these effects are known to contribute to the hematologic manifestations observed during infections.
Scoop.it!
Toll-like receptors engage TIR domain-containing adaptors to control proinflammatory gene expression in response to pathogens and tissue damage.
Scoop.it!
Naive CD4 T-cell maintenance is critical for immune competence. We investigated here the fine-tuning of homeostatic mechanisms of the naive compartment to counteract the loss of de novo CD4 T-cell generation. Adults thymectomized in early childhood during corrective cardiac surgery were grouped based on presence or absence of thymopoiesis and compared with age-matched controls. We found that the preservation of the CD31 subset was independent of the thymus and that its size is tightly controlled by peripheral mechanisms, including prolonged cell survival as attested by Bcl-2 levels. Conversely, a significant contraction of the CD31+ naive subset was observed in the absence of thymic activity. This was associated with impaired responses of purified naive CD4 T-cells to IL-7, namely in vitro proliferation and up-regulation of CD31 expression, which likely potentiated the decline in recent thymic emigrants. Additionally, we found no apparent constraint in the differentiation of naive cells into the memory compartment in individuals completely lacking thymic activity despite upregulation of DUSP6, a phosphatase associated with increased TCR threshold. Of note, thymectomized individuals featuring some degree of thymopoiesis were able to preserve the size and diversity of the naive CD4 compartment, further arguing against complete thymectomy in infancy. Overall, our data suggest that robust peripheral mechanisms ensure the homeostasis of CD31 naive CD4 pool and point to the requirement of continuous thymic activity to the maintenance of IL-7–driven homeostatic proliferation of CD31+ naive CD4 T-cells, which is essential to secure T-cell diversity throughout life.
|
