Search

The immunological synapse is a specialized cell-cell junction between T cell and antigen-presenting cell surfaces. It is characterized by a central cluster of antigen receptors, a ring of integrin family adhesion molecules, and temporal stability over hours. The role of this specific organization in signaling for T cell activation has been controversial. We use in vitro and in silico experiments to determine that the immunological synapse acts as a type of adaptive controller that both boosts T cell receptor triggering and attenuates strong signals., The mature immunological synapse is characterized by a reorganization of membrane proteins, resulting in a stable central cluster of T cell receptors (TCRs) (the C-SMAC) surrounded by a ring of [...]

The area of contact between a T cell and an antigen-presenting cell (APC) is known as the immunological synapse. Although its exact function is unknown, one model suggests that it allows for T cell receptor (TCR) clustering and for sustained signaling in T cells for many hours. Here we demonstrate that TCR-mediated tyrosine kinase signaling in naive T cells occurred primarily at the periphery of the synapse and was largely abated before mature immunological synapses had formed. These data suggest that many hours of TCR signaling are not required for T cell activation. These observations challenge current ideas about the role of immunological synapses in T cell activation., The biochemical pathways that are stimulated by TCR engagement are well characterized, but little is known about how T cell interactions with the APC actually initiate signaling by the TCR. [...]

The T cell receptor (TCR) [Alpha]Β heterodimer interacts with its ligands with high specificity, but surprisingly low affinity. The role of the [Zeta] component of the murine TCR in contributing to the fidelity of antigen recognition was examined. With sequence-specific phosphotyrosine antibodies, it was found that [Zeta] undergoes a series of ordered phosphorylation events upon TCR engagement. Completion of phosphorylation steps is dependent on the nature of the TCR ligand. Thus, the phosphorylation steps establish thresholds for T cell activation. This study documents the sophisticated molecular events that follow the engagement of a low-affinity receptor., The [Alpha]Β TCR is part of a large protein complex composed of the CD3 [Gamma] Δ, [Epsilon], and [Zeta] chains. These chains contain signaling motifs called ITAMs (immune receptor tyrosinebased [...]

Loss of CD2-associated protein (CD2AP), a component of the filtration complex in the kidney, causes death in mice at 6 weeks of age. Mice with CD2AP haploinsufficiency developed glomerular changes at 9 months of age and had increased susceptibility to glomerular injury by nephrotoxic antibodies or immune complexes. Electron microscopic analysis of podocytes revealed defects in the formation of multivesicular bodies, suggesting an impairment of the intracellular degradation pathway. Two human patients with focal segmental glomerulosclerosis had a mutation predicted to ablate expression of one CD2AP allele, implicating CD2AP as a determinant of human susceptibility to glomerular disease., CD2-associated protein (CD2AP) is an Src homology 3 (SH3) domain--containing protein expressed mainly in epithelial and lymphoid cells. Mice completely lacking CD2AP die of massive proteinuria shortly after birth, suggesting [...]

Refining precision medicine with systems biology: Patients with colorectal cancer (CRC) expressing the KRAS G13D mutant often respond to blockade of the growth factor receptor EGFR, whereas CRC patients with all other KRAS mutants do not. Because the reason why this treatment works is unclear in the context of known EGFR-RAS biology, clinical practice generally rejects its use for all KRAS-mutant CRC patients. However, McFall et al. used an integrated computational and biochemical approach to show that compared to other KRAS mutant proteins, KRAS G13D interacted too weakly with the protein NF1 to competitively inhibit it; therefore, wild-type RAS in KRAS G13D cells remains dependent upon EGFR for activation and for tumor growth. These findings reveal why precision medicine would benefit from a more systems-level rather than genomics-level analysis of patients. Cancer treatment decisions are increasingly guided by which specific genes are mutated within each patient's tumor. For example, agents inhibiting the epidermal growth factor receptor (EGFR) benefit many colorectal cancer (CRC) patients, with the general exception of those whose tumor includes a KRAS mutation. However, among the various KRAS mutations, that which encodes the G13D mutant protein (KRASG13D) behaves differently; for unknown reasons, KRASG13D CRC patients benefit from the EGFR-blocking antibody cetuximab. Controversy surrounds this observation, because it contradicts the well-established mechanisms of EGFR signaling with regard to RAS mutations. Here, we identified a systems-level, mechanistic explanation for why KRASG13D cancers respond to EGFR inhibition. A computational model of RAS signaling revealed that the biophysical differences between the three most common KRAS mutants were sufficient to generate different sensitivities to EGFR inhibition. Integrated computation with experimentation then revealed a nonintuitive, mutant-specific dependency of wild-type RAS activation by EGFR that is determined by the interaction strength between KRAS and the tumor suppressor neurofibromin (NF1). KRAS mutants that strongly interacted with and competitively inhibited NF1 drove wild-type RAS activation in an EGFR-independent manner, whereas KRASG13D weakly interacted with and could not competitively inhibit NF1 and, thus, KRASG13D cells remained dependent on EGFR for wild-type RAS activity. Overall, our work demonstrates how systems approaches enable mechanism-based inference in genomic medicine and can help identify patients for selective therapeutic strategies. [ABSTRACT FROM AUTHOR]

CD2-associated protein (CD2AP) is an 80-kilodalton protein that is critical for stabilizing contacts between T cells and antigen-presenting cells. In CD2AP-deficient mice, immune function was compromised, but the mice died at 6 to 7 weeks of age from renal failure. In the kidney, CD2AP was expressed primarily in glomerular epithelial cells. Knockout mice exhibited defects in epithelial cell foot processes, accompanied by mesangial cell hyperplasia and extracellular matrix deposition. Supporting a role for CD2AP in the specialized cell junction known as the slit diaphragm, CD2AP associated with nephrin, the primary component of the slit diaphragm., CD2AP is an adapter protein that interacts with the cytoplasmic domain of CD2 (1). CD2, a T cell and natural killer cell membrane protein, facilitates T cell adhesion to antigen-presenting [...]

The specialized junction between a T lymphocyte and an antigen-presenting cell, the immunological synapse, consists of a central duster of T cell receptors surrounded by a ring of adhesion molecules. Immunological synapse formation is now shown to be an active and dynamic mechanism that allows T cells to distinguish potential antigenic ligands. Initially, T cell receptor ligands were engaged in an outermost ring of the nascent synapse. Transport of these complexes into the central duster was dependent on T cell receptor-ligand interaction kinetics. Finally, formation of a stable central duster at the heart of the synapse was a determinative event for T cell proliferation., A critical event in the initiation of the adaptive immune response is the activation of T lymphocytes. This is mediated by the interaction of T cell antigen receptors (TCRs) with [...]

A central event in the development of immunity is the activation of the T cell. At the center of this process is the T cell receptor (TCR), which triggers activation [...]

Necroptosis, an inflammatory form of cell death, is initiated by the activation of receptor-interacting protein kinase 3 (RIPK3), which depends on its interaction with RIPK1. Although catalytically inactive, the RIPK3 mutant D161N still stimulates RIPK1-dependent apoptosis and embryonic lethality in RIPK3 D161N homozygous mice. Whereas the absence of RIPK1 rescues RIPK3 D161N homozygous mice, we report that the absence of RIPK1 leads to embryonic lethality in RIPK3 D161N heterozygous mice. This suggested that the kinase domain of RIPK3 had a noncatalytic function that was enhanced by a conformation induced by the D161N mutation. We found that the RIPK3 kinase domain homodimerized through a surface that is structurally similar to that of the RAF family members. Mutation of residues at the dimer interface impaired dimerization and necroptosis. Kinase domain dimerization stimulated the activation of RIPK3 through cis-autophosphorylation. This noncatalytic, allosteric activity was enhanced by certain kinase-deficient mutants of RIPK3, including D161N. Furthermore, apoptosis induced by certain RIPK3 inhibitors was also dependent on the kinase dimerization interface. Our studies reveal that the RIPK3 kinase domain exhibits catalytically independent function that is important for both RIPK3-dependent necroptosis and apoptosis. [ABSTRACT FROM AUTHOR]

Examines the role of the ...component of the murine t cell receptor (TCR) in contributing to the fidelity of antigen recognition. How the TCR alpha-beta heterodimer interacts with ligands with high specifity but low affinity; Documentation of the molecular events that follow the engagement of the low-affinity receptor.

The article discusses the presence of microtubule structure that extend from cell surface enabling motility and signal transduction known as cilia in T-lymphocytes and informs that in previous studies cilia have not been found in lymphocytes.

The article reports on the impact of blockade in calcium channel on chronic kidney disease (CKD). Topics discussed include several cause of chronic kidney disease such as obesity, hypertension and diabetes, increase in the risk of end-stage renal disease (ESRD) and role of transient receptor potential canonical-5 (TRPC5).

The article discusses two reports within the issue regarding immunology research in which both scientific teams demonstrate a part of the mechanism that alerts sentinel cells embedded in the skin and mucosa that it has been breached by a pathogen. Topics include an overview of the physiology of skin and various skin proteins, including the immunoglobulin superfamily (IgSF), which facilitates the transient opening of epithelial barriers to allow the passage of cells in tight junctions, and the junctional adhesion molecule-like proteins (JAMLs), which facilitates neutrophil chemotaxis across endothelial cells. Also discussed is the sentinel skin cell γδ, which is an epidermal T cell that responds to injury and infection when stimulated by a cellular adhesion protein.

The immunological synapse is a specialized cell-cell junction between T cell and antigen-presenting cell surfaces. It is characterized by a central cluster of antigen receptors, a ring of integrin family adhesion molecules, and temporal stability over hours. The role of this specific organization in signaling for T cell activation has been controversial. We use in vitro and in silico experiments to determine that the immunological synapse acts as a type of adaptive controller that both boosts T cell receptor triggering and attenuates strong signals. [ABSTRACT FROM AUTHOR]

The area of contact between a T cell and an antigen-presenting cell (APC) is known as the immunological synapse. Although its exact function is unknown, one model suggests that it allows for T cell receptor (TCR) clustering and for sustained signaling in T cells for many hours. Here we demonstrate that TCR-mediated tyrosine kinase signaling in naïve T cells occurred primarily at the periphery of the synapse and was largely abated before mature immunological synapses had formed. These data suggest that many hours of TCR signaling are not required for T cell activation. These observations challenge current ideas about the role of immunological synapses in T cell activation. [ABSTRACT FROM AUTHOR]

Precise regulation of the kinetics and magnitude of Ca(2+) signaling enables this signal to mediate diverse responses, such as cell migration, differentiation, vesicular trafficking, and cell death. We showed that the Ca(2+)-binding protein calmodulin (CaM) acted in a positive feedback loop to potentiate Ca(2+) signaling downstream of the Tec kinase family member Itk. Using NMR (nuclear magnetic resonance), we mapped CaM binding to two loops adjacent to the lipid-binding pocket within the Itk pleckstrin homology (PH) domain. The Itk PH domain bound synergistically to Ca(2+)/CaM and the lipid phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], such that binding to Ca(2+)/CaM enhanced the binding to PI(3,4,5)P3 and vice versa. Disruption of CaM binding attenuated Itk recruitment to the membrane and diminished release of Ca(2+) from the endoplasmic reticulum. Moreover, disruption of this feedback loop abrogated Itk-dependent production of the proinflammatory cytokine IL-17A (interleukin-17A) by CD4(+) T cells. Additionally, we found that CaM associated with PH domains from other proteins, indicating that CaM may regulate other PH domain-containing proteins., (Copyright © 2014, American Association for the Advancement of Science.)