scholarly journals Poor correlation between T-cell activation assays and HLA-DR binding prediction algorithms in an immunogenic fragment of Pseudomonas exotoxin A

2015 ◽  
Vol 425 ◽  
pp. 10-20 ◽  
Author(s):  
Ronit Mazor ◽  
Chin-Hsien Tai ◽  
Byungkook Lee ◽  
Ira Pastan
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Poor Correlation ◽  
Exotoxin A ◽  
Binding Prediction ◽  
Pseudomonas Exotoxin ◽  
Pseudomonas Exotoxin A ◽  
Prediction Algorithms ◽  
Hla Dr

scholarly journals Antiretroviral Therapy Reduces T-cell Activation and Immune Exhaustion Markers in Human Immunodeficiency Virus Controllers

2019 ◽  
Vol 70 (8) ◽  
pp. 1636-1642 ◽  
Author(s):  
Jonathan Z Li ◽  
Florencia P Segal ◽  
Ronald J Bosch ◽  
Christina M Lalama ◽  
Carla Roberts-Toler ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Residual Viremia ◽  
Cd4 Counts ◽  
Hiv Rna ◽  
Immune Exhaustion ◽  
Hla Dr ◽  
Immunodeficiency Virus ◽  
Hiv Controllers

Abstract Background Despite low plasma human immunodeficiency virus (HIV) RNA, HIV controllers have evidence of viral replication and elevated inflammation. We assessed the effect of antiretroviral therapy (ART) on HIV suppression, immune activation, and quality of life (QoL). Methods A5308 was a prospective, open-label study of rilpivirine/emtricitabine/tenofovir disoproxil fumarate in ART-naive HIV controllers (N = 35), defined as having HIV RNA <500 copies/mL for ≥12 months. The primary outcome measured change in %CD38+HLA-DR+ CD8+ T cells. Residual plasma viremia was measured using the integrase single-copy assay. QoL was measured using the EQ-5D questionnaire. Outcomes were evaluated using repeated measures general estimating equations models. Results Before ART, HIV controllers with undetectable residual viremia <0.6 HIV-1 RNA copies/mL had higher CD4+ counts and lower levels of T-cell activation than those with detectable residual viremia. ART use was effective in further increasing the proportion of individuals with undetectable residual viremia (pre-ART vs after 24–48 weeks of ART: 19% vs 94%, P < .001). Significant declines were observed in the %CD38+HLA-DR+CD8+ T cells at 24–48 (−4.0%, P = .001) and 72–96 (−7.2%, P < .001) weeks after ART initiation. ART use resulted in decreases of several cellular markers of immune exhaustion and in a modest but significant improvement in self-reported QoL. There were no significant changes in CD4+ counts or HIV DNA. Conclusions ART in HIV controllers reduces T-cell activation and improves markers of immune exhaustion. These results support the possible clinical benefits of ART in this population.

Evidence for Kupffer cell activation by burn injury and pseudomonas exotoxin A

Burns ◽  
1993 ◽  
Vol 19 (1) ◽  
pp. 12-16 ◽  
Author(s):  
Y-L. Dong ◽  
F. Ko ◽  
T. Yan ◽  
H-Q. Huang ◽  
D.N. Herndon ◽  
...  
Keyword(s):  
Kupffer Cell ◽  
Cell Activation ◽  
Burn Injury ◽  
Exotoxin A ◽  
Pseudomonas Exotoxin ◽  
Pseudomonas Exotoxin A

scholarly journals Introduction of Non-natural Amino Acids Into T-Cell Epitopes to Mitigate Peptide-Specific T-Cell Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Aurélien Azam ◽  
Sergio Mallart ◽  
Stephane Illiano ◽  
Olivier Duclos ◽  
Catherine Prades ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Epitope ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Anchor Residue ◽  
Hla Dr

Non-natural modifications are widely introduced into peptides to improve their therapeutic efficacy, but their impact on immunogenicity remains largely unknown. As the CD4 T-cell response is a key factor in triggering immunogenicity, we investigated the effect of introducing D-amino acids (Daa), amino isobutyric acid (Aib), N-methylation, Cα-methylation, reduced amide, and peptoid bonds into an immunoprevalent T-cell epitope on binding to a set of HLA-DR molecules, recognition, and priming of human T cells. Modifications are differentially accepted at multiple positions, but are all tolerated in the flanking regions. Introduction of Aib and Daa in the binding core had the most deleterious effect on binding to HLA-DR molecules and T-cell activation. Their introduction at the positions close to the P1 anchor residue abolished T-cell priming, suggesting they might be sufficient to dampen peptide immunogenicity. Other modifications led to variable effects on binding to HLA-DR molecules and T-cell reactivity, but none exhibited an increased ability to stimulate T cells. Altogether, non-natural modifications appear generally to diminish binding to HLA-DR molecules and hence T-cell stimulation. These data might guide the design of therapeutic peptides to make them less immunogenic.

scholarly journals Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation

Blood ◽  
2021 ◽  
Author(s):  
Livius Penter ◽  
Yi Zhang ◽  
Alexandra Savell ◽  
Teddy Huang ◽  
Nicoletta Cieri ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
T Cell Infiltration ◽  
Graft Versus Leukemia ◽  
Hla Dr ◽  
Cellular Pathways

Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade (ICB) in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GvL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the ETCTN 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T cell populations and increased expression of markers of T cell activation and co-stimulation such as PD-1, HLA-DR and ICOS, irrespective of response. However, responding patients were characterized by higher turnover of T cell receptor sequences in peripheral blood and showed increased expression of proinflammatory chemokines in plasma that was further amplified by ipilimumab. Altogether, these data highlight the compositional T cell shifts and inflammatory pathways induced by ipilimumab both locally and systemically that associate with successful GvL outcomes.

scholarly journals Immune activation correlates with and predicts CXCR4 co-receptor tropism switch in HIV-1 infection

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Bridgette J. Connell ◽  
Lucas E. Hermans ◽  
Annemarie M. J. Wensing ◽  
Ingrid Schellens ◽  
Pauline J. Schipper ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Causative Role ◽  
Subtype C ◽  
Subtype B ◽  
Hla Dr ◽  
Immunological Factors ◽  
Hiv 1

Abstract HIV-1 cell entry is mediated by binding to the CD4-receptor and chemokine co-receptors CCR5 (R5) or CXCR4 (X4). R5-tropic viruses are predominantly detected during early infection. A switch to X4-tropism often occurs during the course of infection. X4-tropism switching is strongly associated with accelerated disease progression and jeopardizes CCR5-based HIV-1 cure strategies. It is unclear whether host immunological factors play a causative role in tropism switching. We investigated the relationship between immunological factors and X4-tropism in a cross-sectional study in HIV-1 subtype C (HIV-1C)-infected patients and in a longitudinal HIV-1 subtype B (HIV-1B) seroconverter cohort. Principal component analysis identified a cluster of immunological markers (%HLA-DR+ CD4+ T-cells, %CD38+HLA-DR+ CD4+ T-cells, %CD38+HLA-DR+ CD8+ T-cells, %CD70+ CD4+ T-cells, %CD169+ monocytes, and absolute CD4+ T-cell count) in HIV-1C patients that was independently associated with X4-tropism (aOR 1.044, 95% CI 1.003–1.087, p = 0.0392). Analysis of individual cluster contributors revealed strong correlations of two markers of T-cell activation (%HLA-DR+ CD4+ T-cells, %HLA-DR+CD38+ CD4+ T-cells) with X4-tropism, both in HIV-1C patients (p = 0.01;p = 0.03) and HIV-1B patients (p = 0.0003;p = 0.0001). Follow-up data from HIV-1B patients subsequently revealed that T-cell activation precedes and independently predicts X4-tropism switching (aHR 1.186, 95% CI 1.065–1.321, p = 0.002), providing novel insights into HIV-1 pathogenesis and CCR5-based curative strategies.

scholarly journals Distinct Mechanisms of CD4+ and CD8+ T-Cell Activation and Bystander Apoptosis Induced by Human Immunodeficiency Virus Type 1 Virions

2005 ◽  
Vol 79 (10) ◽  
pp. 6299-6311 ◽  
Author(s):  
Geoffrey H. Holm ◽  
Dana Gabuzda
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Hla Dr ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Apoptosis of uninfected bystander T cells contributes to T-cell depletion during human immunodeficiency virus type 1 (HIV-1) infection. HIV-1 envelope/receptor interactions and immune activation have been implicated as contributors to bystander apoptosis. To better understand the relationship between T-cell activation and bystander apoptosis during HIV-1 pathogenesis, we investigated the effects of the highly cytopathic CXCR4-tropic HIV-1 variant ELI6 on primary CD4+ and CD8+ T cells. Infection of primary T-cell cultures with ELI6 induced CD4+ T-cell depletion by direct cell lysis and bystander apoptosis. Exposure of primary CD4+ and CD8+ T cells to nonreplicating ELI6 virions induced bystander apoptosis through a Fas-independent mechanism. Bystander apoptosis of CD4+ T cells required direct contact with virions and Env/CXCR4 binding. In contrast, the apoptosis of CD8+ T cells was triggered by a soluble factor(s) secreted by CD4+ T cells. HIV-1 virions activated CD4+ and CD8+ T cells to express CD25 and HLA-DR and preferentially induced apoptosis in CD25+HLA-DR+ T cells in a CXCR4-dependent manner. Maximal levels of binding, activation, and apoptosis were induced by virions that incorporated MHC class II and B7-2 into the viral membrane. These results suggest that nonreplicating HIV-1 virions contribute to chronic immune activation and T-cell depletion during HIV-1 pathogenesis by activating CD4+ and CD8+ T cells, which then proceed to die via apoptosis. This mechanism may represent a viral immune evasion strategy to increase viral replication by activating target cells while killing immune effector cells that are not productively infected.

scholarly journals Impact of HLA-DR Antigen Binding Cleft Rigidity on T Cell Recognition

2020 ◽  
Vol 21 (19) ◽  
pp. 7081
Author(s):  
Christopher Szeto ◽  
Joseph I. Bloom ◽  
Hannah Sloane ◽  
Christian A. Lobos ◽  
James Fodor ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Stability ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Leukocyte ◽  
Antigen Binding ◽  
Hla Class I Molecules ◽  
Hla Dr ◽  
Binding Cleft

The interaction between T cell receptor (TCR) and peptide (p)-Human Leukocyte Antigen (HLA) complexes is the critical first step in determining T cell responses. X-ray crystallographic studies of pHLA in TCR-bound and free states provide a structural perspective that can help understand T cell activation. These structures represent a static “snapshot”, yet the nature of pHLAs and their interactions with TCRs are highly dynamic. This has been demonstrated for HLA class I molecules with in silico techniques showing that some interactions, thought to stabilise pHLA-I, are only transient and prone to high flexibility. Here, we investigated the dynamics of HLA class II molecules by focusing on three allomorphs (HLA-DR1, -DR11 and -DR15) that are able to present the same epitope and activate CD4+ T cells. A single TCR (F24) has been shown to recognise all three HLA-DR molecules, albeit with different affinities. Using molecular dynamics and crystallographic ensemble refinement, we investigate the molecular basis of these different affinities and uncover hidden roles for HLA polymorphic residues. These polymorphisms were responsible for the widening of the antigen binding cleft and disruption of pHLA-TCR interactions, underpinning the hierarchy of F24 TCR binding affinity, and ultimately T cell activation. We expanded this approach to all available pHLA-DR structures and discovered that all HLA-DR molecules were inherently rigid. Together with in vitro protein stability and peptide affinity measurements, our results suggest that HLA-DR1 possesses inherently high protein stability, and low HLA-DM susceptibility.

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