Abstract Ag-specific T cell tolerance plays a critical role in tumor escape. Recent studies implicated myeloid-derived suppressor cells (MDSCs) the induction of CD8+ tumor-bearing hosts. However, mechanism this phenomenon remained unclear. We have found that incubation cells, with peptide-loaded MDSCs, did not induce signaling downstream TCR. it prevented subsequent from dendritic cells. Using double TCR transgenic we demonstrated MDSC induced to only peptide, which was presented by MDSCs....

Following infection, naïve CD8 + T cells bearing pathogen-specific cell receptors (TCRs) differentiate into a mixed population of short-lived effector and long-lived memory to mediate an adaptive immune response. How the TCR regulates development has remained elusive. Using mutant transgenic model, we found that point mutations in β transmembrane domain (βTMD) impair function without affecting primary responses. Mutant are deficient polarizing organizing nuclear factor κB signal at...

Abstract Quantitation of huntingtin protein in the brain is needed, both as a marker Huntington disease (HD) progression and for use clinical gene silencing trials. Measurement cerebrospinal fluid could be biomarker huntingtin, but traditional quantitation methods have failed to detect fluid. Using micro-bead based immunoprecipitation flow cytometry (IP-FCM), we developed highly sensitive mutant detection assay. The sensitivity IP-FCM enables accurate HD patients model mice, demonstrating...

The T cell receptor (TCR) can recognize a variety of cognate peptide/major histocompatibility complex (pMHC) ligands and translate their affinity into distinct cellular responses. To achieve this, the nonsignaling αβ heterodimer communicates ligand recognition to CD3 signaling subunits by an unknown mechanism. In thymocytes, we found that both positive- negative-selecting pMHC expose cryptic epitope in upon TCR engagement. This conformational change is induced vivo requires expression MHC....

In many cell types agonist-receptor activation leads to a rapid and transient release of Ca2+ from intracellular stores via inositol 1,4,5 trisphosphate (InsP3) receptors (InsP3Rs). Stimulated cells activate store- or receptor-operated calcium channels localized in the plasma membrane, allowing entry extracellular into cytoplasm, thus replenishment stores. Calcium must be finely regulated order prevent an excessive increase. Junctate, integral binding protein endo(sarco)plasmic reticulum (a)...

We propose a likely contribution to severe COVID-19 morbidity by extracellular DNA in neutrophil traps (NETs). Dornase alfa degrades reduce mucus rigidity and accumulation, was associated with respiratory improvement first patient. should be considered for clinical trials treatment of COVID-19.

The most severe cases of Coronavirus-Disease-2019 (COVID-19) develop into Acute Respiratory Distress Syndrome (ARDS). It has been proposed that oxygenation may be inhibited by extracellular deoxyribonucleic acid (DNA) in the form neutrophil traps (NETs). Dornase alfa (Pulmozyme, Genentech) is recombinant human deoxyribonuclease I acts as a mucolytic cleaving and degrading DNA. We performed pilot study to evaluate effects dornase patients with ARDS secondary COVID-19.We pilot, non-randomized,...

Monoclonal antibodies (mAbs) have proven to be useful for development of new therapeutic drugs and diagnostic techniques. To overcome the difficulties posed by their complex structure folding, reduce undesired immunogenicity, improve pharmacoki- netic properties, a plethora different Ab fragments been developed. These include recombinant Fab Fv segments that can display improved properties over those original mAbs upon which they are based. Antibody (Ab) such as Fabs, scFvs, diabodies,...

Autism spectrum disorders (ASDs) are a heterogeneous group of behaviorally defined and associated with hundreds rare genetic mutations several environmental risk factors. Mouse models specific factors have been successful in identifying molecular mechanisms given factor. However, comparisons among different to elucidate underlying common pathways or define clusters biologically relevant disease subtypes complicated by methodological approaches brain regions examined the labs that developed...

The Omicron variant of SARS-CoV-2 bears peptide sequence alterations that correlate with a higher infectivity than was observed in the original isolated from Wuhan, China. We analyzed CendR motif spike protein and performed silico molecular docking neuropilin-1 (Nrp1), receptor-ligand interaction known to support infection by variant. Our analysis predicts conserved slightly increased energetic favorability binding for CendR:Nrp1. propose viral spike:Nrp1 coreceptor pathway may contribute SARS-CoV-2.

Background/Objectives: Peptide amphiphile micelles (PAMs) are an exciting nanotechnology currently being studied for a variety of biomedical applications, especially drug delivery. Specifically, PAMs can enhance in vivo trafficking, cell-targeting, and cell interactions/internalization. However, modifying peptides, as is commonly performed to induce micellization, influence their bioactivity. In our previous work, murine antibody responses containing the influenza antigen M22–16 were...

Vasoactive intestinal peptide (VIP) is a promising anti-inflammatory therapeutic that known to induce biological effects by interacting with its cognate receptor (i.e., VPAC) on the surface of antigen...

Background: Peptide amphiphile micelles (PAMs) are a promising lipid-based nanotechnology currently in development for variety of applications ranging from atherosclerosis to cancer therapy. Especially relevant immune applications, PAMs improve trafficking through lymphatic vessels, enhance uptake by antigen-presenting cells, and inhibit the protease-mediated degradation cargo. However, creation peptide amphiphiles (PAs) necessary induce micellization often requires modifying an immunotarget...

Abstract Cancer patients treated with immune checkpoint inhibition (ICI), such as monoclonal antibodies (mAbs) that block the inhibitory functions of T cell receptors, CTLA-4 and PD-1, are at risk experiencing immune-related adverse effects (IRAEs). These may require interruption, neutralization, or discontinuation treatments, potentially hindering control cancer progression. The for IRAEs is elevated in individuals underlying autoimmune diseases (AIDs), resulting this subpopulation being...

T cell responses are compromised in the elderly. The B7-CD28 family receptors critical regulation of immune responses. We evaluated whether B7-family and CD28-family were differentially expressed dendritic cells, macrophages, CD4(+) CD8(+) cells from young old mice, which could contribute to dysfunction old. Although most equally all >85% naive B7-H1 compared with 25% young. Considering that negatively regulates responses, we hypothesized expression would downregulate function cells. Old...

Multiprotein complexes transduce cellular signals through extensive interaction networks, but the ability to analyze these networks in cells from small clinical biopsies is limited. To address this, we applied an adaptable multiplex matrix system physiologically relevant signaling protein isolated a cell line or human patient samples. Focusing on proximal T receptor (TCR) signalosome, assessed 210 pairs of PiSCES (proteins shared detected by exposed surface epitopes). Upon stimulation Jurkat...

Abstract CD8 T cells must integrate antigenic and inflammatory signals to differentiate into efficient effector memory able protect us from infections. The mechanisms by which TCR signaling proinflammatory cytokine receptor cooperate in these processes are poorly defined. In this study, we show that IL-12 other cytokines transduce through the signalosome a manner requires Fyn activity self-peptide–MHC (self-pMHC) interactions. This mechanism is crucial for innate cell functions. Loss of or...

In the lungs of infected individuals, downstream molecular signaling pathways induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are incompletely understood. Here, we describe and examine predictions a model in which NOTCH may represent central axis lung infection Disease 2019 (COVID-19). A pathway involving signaling, furin, ADAM17, ACE2 be capable increasing SARS-CoV-2 viral entry infection. can also upregulate IL-6 pro-inflammatory mediators to hyperactivation...

Strong antigenic encounter by T cells rapidly induces immunological synapse formation and surface cell receptor (TCR) downregulation. Although TCR expression can remain low for several days, still sustain signaling. It has been unclear whether prolonged signaling occurs in the absence of replenishment, being maintained a few “nondownregulatable” TCRs that might reside synaptosomal structure. Alternatively, level induced antigen represent dynamic state involving continual reengagement...

Most mechanisms of cell development, physiology, and signal transduction are controlled by protein-protein interactions. Immunoprecipitation multiprotein complexes detected flow cytometry (IP-FCM) is a means to quantitatively measure these The high sensitivity this method makes it useful even when very little biomaterial available for analysis, as in the case rare primary subsets or patient samples. Detection T antigen receptor associated with CD3 complex from few 300 murine cells presented...

Most immunocompetent patients diagnosed with latent tuberculosis infection (LTBI) will not progress to (TB) reactivation. However, current diagnostic tools cannot reliably distinguish nonprogressing from progressing a priori, and thus LTBI therapy must be prescribed suboptimal patient specificity. We hypothesized that diagnostics could improved by generating immunomarker profiles capable of categorizing distinct subsets combinatorial immunoassay approach.A analysis was applied identify...