Receptors carrying immunoreceptor tyrosine-based inhibition motifs (ITIMs) in their cytoplasmic tail control a vast array of cellular responses, ranging from autoimmunity, allergy, phagocytosis of ...red blood cells, graft versus host disease, to even neuronal plasticity in the brain. The inhibitory function of many receptors has been deduced on the basis of cytoplasmic ITIM sequences. Tight regulation of natural killer (NK) cell cytotoxicity and cytokine production by inhibitory receptors specific for major histocompatibility complex class I molecules has served as a model system to study the negative signaling pathway triggered by an ITIM-containing receptor in the physiological context of NK-target cell interactions. Advances in our understanding of the molecular details of inhibitory signaling in NK cells have provided a conceptual framework to address how ITIM-mediated regulation controls cellular reactivity in diverse cell types.
Understanding how signals are integrated to control natural killer (NK) cell responsiveness in the absence of antigen-specific receptors has been a challenge, but recent work has revealed some ...underlying principles that govern NK cell responses. NK cells use an array of innate receptors to sense their environment and respond to alterations caused by infections, cellular stress, and transformation. No single activation receptor dominates; instead, synergistic signals from combinations of receptors are integrated to activate natural cytotoxicity and cytokine production. Inhibitory receptors for major histocompatibility complex class I (MHC-I) have a critical role in controlling NK cell responses and, paradoxically, in maintaining NK cells in a state of responsiveness to subsequent activation events, a process referred to as licensing. MHC-I-specific inhibitory receptors both block activation signals and trigger signals to phosphorylate and inactivate the small adaptor Crk. These different facets of inhibitory signaling are incorporated into a revocable license model for the reversible tuning of NK cell responsiveness.
Natural killer (NK) cells, which have an essential role in immune defense, also contribute to reproductive success. NK cells are abundant at the maternal–fetal interface, where soluble HLA-G is ...produced by fetal trophoblast cells during early pregnancy. Soluble HLA-G induces a proinflammatory response in primary, resting NK cells on endocytosis into early endosomes where its receptor, CD158d, resides. CD158d initiates signaling through DNA-PKcs, Akt, and NF-κB for a proinflammatory and proangiogenic response. The physiological relevance of this endosomal signaling pathway, and how activation of CD158d through soluble ligands regulates NK cell fate and function is unknown. We show here that CD158d agonists trigger a DNA damage response signaling pathway involving cyclin-dependent kinase inhibitor p21 expression and heterochromatin protein HP1-γ phosphorylation. Sustained activation through CD158d induced morphological changes in NK cell shape and size, and survival in the absence of cell-cycle entry, all hallmarks of senescence, and a transcriptional signature of a senescence-associated secretory phenotype (SASP). SASP is a program that can be induced by oncogenes or DNA damage, and promotes growth arrest and tissue repair. The secretome of CD158d-stimulated senescent NK cells promoted vascular remodeling and angiogenesis as assessed by functional readouts of vascular permeability and endothelial cell tube formation. Retrospective analysis of the decidual NK cell transcriptome revealed a strong senescence signature. We propose that a positive function of senescence in healthy tissue is to favor reproduction through the sustained activation of NK cells to remodel maternal vasculature in early pregnancy.
Natural killer (NK)–cell recognition of infected or neoplastic cells can induce cytotoxicity and cytokine secretion. So far, it has been difficult to assess the relative contribution of multiple ...NK-cell activation receptors to cytokine and chemokine production upon target cell recognition. Using Drosophila cells expressing ligands for the NK-cell receptors LFA-1, NKG2D, DNAM-1, 2B4, and CD16, we studied the minimal requirements for secretion by freshly isolated, human NK cells. Target cell stimulation induced secretion of predominately proinflammatory cytokines and chemokines. Release of chemokines MIP-1α, MIP-1β, and RANTES was induced within 1 hour of stimulation, whereas release of TNF-α and IFN-γ occurred later. Engagement of CD16, 2B4, or NKG2D sufficed for chemokine release, whereas induction of TNF-α and IFN-γ required engagement of additional receptors. Remarkably, our results revealed that, upon target cell recognition, CD56dim NK cells were more prominent cytokine and chemokine producers than CD56bright NK cells. The present data demonstrate how specific target cell ligands dictate qualitative and temporal aspects of NK-cell cytokine and chemokine responses. Conceptually, the results point to CD56dim NK cells as an important source of cytokines and chemokines upon recognition of aberrant cells, producing graded responses depending on the multiplicity of activating receptors engaged.
Key message
In this present study, we introduce a fundamental framework and provide information regarding the possible roles of GDSL-type esterase/lipase gene family in
Arabidopsis
.
GDSL-type ...esterases/lipases are hydrolytic enzymes with multifunctional properties such as broad substrate specificity, regiospecificity, and stereoselectivity. In this study, we identified 105
GDSL-type esterase
/
lipase
genes in
Arabidopsis thaliana
by conducting a comprehensive computational analysis. Expression studies indicated that GDSL-type lipase proteins showed varied expression patterns. Phylogenetic tree analysis indicated that
AtGELP
(
Arabidopsis thaliana
GDSL-type esterase/lipase protein) gene family was divided into four clades. The phylogenetic analysis, combined with protein motif architectures, and expression profiling were used to predict the roles
AtGELP
genes. To investigate the physical roles of the
AtGELP
gene family, we successfully screened 88
AtGELP
T-DNA knockout lines for 54
AtGELP
genes from 199 putative SALK T-DNA mutants. Transgenic plants of
AtGELP
genes were used to elucidate the phenotypic characteristics in various developmental stages or stress conditions. Our results suggest that the
AtGELP
genes have diverse physical functions such as affecting the germination rate and early growth of seedlings subjected to high concentrations of glucose, or being involved in biotic stress responses.
Natural killer (NK) cell inhibitory receptors recruit tyrosine phosphatases to prevent activation, induce phosphorylation and dissociation of the small adaptor Crk from cytoskeleton scaffold ...complexes, and maintain NK cells in a state of responsiveness to subsequent activation events. How Crk contributes to inhibition is unknown. We imaged primary NK cells over lipid bilayers carrying IgG1 Fc to stimulate CD16 and human leukocyte antigen (HLA)-E to inhibit through receptor CD94-NKG2A. HLA-E alone induced Crk phosphorylation in NKG2A+ NK cells. At activating synapses with Fc alone, Crk was required for the movement of Fc microclusters and their ability to trigger activation signals. At inhibitory synapses, HLA-E promoted central accumulation of both Fc and phosphorylated Crk and blocked the Fc-induced buildup of F-actin. We propose a unified model for inhibitory receptor function: Crk phosphorylation prevents essential Crk-dependent activation signals and blocks F-actin network formation, thereby reducing constraints on subsequent engagement of activation receptors.
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► Inhibitory receptor NKG2A binding to HLA-E induces phosphorylation of adaptor Crk ► Crk is required for activation signals and for movement of receptor microclusters ► Activation receptors and phospho-Crk accumulate at the center of inhibitory synapses ► Crk is required for the HLA-E-mediated inhibition of F-actin accumulation
Major histocompatibility complex class I-specific inhibitory receptors on
natural killer cells prevent the lysis of healthy autologous cells. The outcome
of this negative signal is not anergy or ...apoptosis of natural killer cells but
a transient abortion of activation signals. The natural killer inhibitory
receptors fulfill this function by recruiting the tyrosine phosphatase SHP-1
through a cytoplasmic immunoreceptor tyrosine-based inhibition motif. This
immunoreceptor tyrosine-based inhibition motif has become the hallmark of a
growing family of receptors with inhibitory potential, which are expressed in
various cell types such as monocytes, macrophages, dendritic cells, leukocytes,
and mast cells. Most of the natural killer inhibitory receptors and two members
of a monocyte inhibitory-receptor family bind major histocompatibility complex
class I molecules. Ligands for many of the other receptors have yet to be
identified. The inhibitory-receptor superfamily appears to regulate many types
of immune responses by blocking cellular activation signals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Natural killer (NK) cells provide innate control of infected and neoplastic cells. Multiple receptors have been implicated in natural cytotoxicity, but their individual contribution remains unclear. ...Here, we studied the activation of primary, resting human NK cells by Drosophila cells expressing ligands for receptors NKG2D, DNAM-1, 2B4, CD2, and LFA-1. Each receptor was capable of inducing inside-out signals for LFA-1, promoting adhesion, but none induced degranulation. Rather, release of cytolytic granules required synergistic activation through coengagement of receptors, shown here for NKG2D and 2B4. Although engagement of NKG2D and 2B4 was not sufficient for strong target cell lysis, collective engagement of LFA-1, NKG2D, and 2B4 defined a minimal requirement for natural cytotoxicity. Remarkably, inside-out signaling induced by each one of these receptors, including LFA-1, was inhibited by receptor CD94/NKG2A binding to HLA-E. Strong inside-out signals induced by the combination of NKG2D and 2B4 or by CD16 could overcome CD94/NKG2A inhibition. In contrast, degranulation induced by these receptors was still subject to inhibition by CD94/NKG2A. These results reveal multiple layers in the activation pathway for natural cytotoxicity and that steps as distinct as inside-out signaling to LFA-1 and signals for granule release are sensitive to inhibition by CD94/NKG2A.
Cytotoxic immunological synapses Dustin, Michael L; Long, Eric O
Immunological reviews,
20/May , Letnik:
235, Številka:
1
Journal Article
Recenzirano
Odprti dostop
One of the most fundamental activities of the adaptive immune system is to kill infected cells and tumor cells. Two distinct pathways mediate this process, both of which are facilitated by a ...cytotoxic immunological synapse. While traditionally thought of as innate immune cells, natural killer (NK) cells are now appreciated to have the capacity for long-term adaptation to chemical and viral insults. These cells integrate multiple positive and negative signals through NK cell cytotoxic or inhibitory synapses. The traditional CD8⁺αβ T-cell receptor-positive cells are among the best models for the concept of an immunological synapse, in which vectoral signaling is linked to directed secretion in a stable interface to induce apoptotic cell death in an infected cell. Large-scale molecular organization in synapses generated a number of hypotheses. Studies in the past 5 years have started to provide clear answers regarding the validity of these models. In vivo imaging approaches have provided some hints as to the physiologic relevance of these processes with great promise for the future. This review provides an overview of work on cytotoxic immunological synapses and suggests pathways forward in applying this information to the development of therapeutic agents.
Natural killer (NK) cells possess potent cytolytic activity and secrete immune modulating cytokines. The large repertoire of NK cell receptors provides versatility for the identification of infected ...and transformed cells and for their elimination by NK cells. NK cell responses also stimulate and regulate the adaptive arm of the immune system. We review current knowledge about the molecular specificity of NK cell receptors and about the regulation of NK cell effector functions upon encounter with target cells. Mechanisms of recognition, interplay among receptors, signal integration, and the dynamic fine-tuning of NK cell responses are discussed. New insights into the molecular checkpoints for NK cell effector function are highlighted, and underlying reasons for the complexity in NK cell recognition and signaling are proposed.
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