scholarly journals Latency reversal agents modulate HIV antigen processing and presentation to CD8 T cells

2020 ◽  
Vol 16 (3) ◽  
pp. e1008442
Author(s):  
Julie Boucau ◽  
Jishnu Das ◽  
Neelambari Joshi ◽  
Sylvie Le Gall
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Reversal Agents ◽  
Hiv Antigen ◽  
Antigen Processing And Presentation ◽  
Latency Reversal Agents

scholarly journals Cross-presentation of a TAP-independent signal peptide induces CD8 T immunity to escaped cancers but necessitates anchor replacement

2021 ◽  
Author(s):  
Koen A. Marijt ◽  
Lisa Griffioen ◽  
Laura Blijleven ◽  
Sjoerd. H. van der Burg ◽  
Thorbald van Hall
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Signal Sequence ◽  
Cell Repertoire ◽  
Cross Presentation ◽  
Normal Tissues ◽  
Cell Immunity

AbstractCancer cells frequently display defects in their antigen-processing pathway and thereby evade CD8 T cell immunity. We described a novel category of cancer antigens, named TEIPP, that emerge on cancers with functional loss of the peptide pump TAP. TEIPPs are non-mutated neoantigens despite their ‘self’ origin by virtue of their absence on normal tissues. Here, we describe the development of a synthetic long peptide (SLP) vaccine for the most immunogenic TEIPP antigen identified thus far, derived from the TAP-independent LRPAP1 signal sequence. LRPAP121–30-specific CD8 T cells were present in blood of all tested healthy donors as well as patients with non-small cell lung adenocarcinoma. SLPs with natural flanking, however, failed to be cross-presented by monocyte-derived dendritic cells. Since the C-terminus of LRPAP121–30 is an unconventional and weakly binding serine (S), we investigated if replacement of this anchor would result in efficient cross-presentation. Exchange into a valine (V) resulted in higher HLA-A2 binding affinity and enhanced T cell stimulation. Importantly, CD8 T cells isolated using the V-variant were able to bind tetramers with the natural S-variant and respond to TAP-deficient cancer cells. A functional screen with an array of N-terminal and C-terminal extended SLPs pointed at the 24-mer V-SLP, elongated at the N-terminus, as most optimal vaccine candidate. This SLP was efficiently cross-presented and consistently induced a strong polyclonal LRPAP121–30-specific CD8 T cells from the endogenous T cell repertoire. Thus, we designed a TEIPP SLP vaccine from the LRPAP1 signal sequence ready for validation in clinical trials.

scholarly journals Lack of tumor recognition by hTERT peptide 540-548-specific CD8+ T cells from melanoma patients reveals inefficient antigen processing

2001 ◽  
Vol 31 (9) ◽  
pp. 2642-2651 ◽  
Author(s):  
Maha Ayyoub ◽  
Marco Migliaccio ◽  
Philippe Guillaume ◽  
Danielle Liénard ◽  
Jean-Charles Cerottini ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Tumor Recognition ◽  
Melanoma Patients

HIV Antigen Processing and Presentation

2014 ◽  
pp. 1-8
Author(s):  
Julie Boucau ◽  
Marijana Rucevic ◽  
Sylvie Le Gall
Keyword(s):  
Antigen Processing ◽  
Hiv Antigen ◽  
Antigen Processing And Presentation

Bryostatin-1 decreases HIV-1 infection and viral production in human primary macrophages

2021 ◽  
Author(s):  
Laurent Hany ◽  
Marc-Olivier Turmel ◽  
Corinne Barat ◽  
Michel Ouellet ◽  
Michel J. Tremblay
Keyword(s):  
T Cells ◽  
Myeloid Cells ◽  
People Living With Hiv ◽  
Bryostatin 1 ◽  
Viral Production ◽  
Human Macrophages ◽  
Reversal Agents ◽  
Infected Cells ◽  
Hiv 1 ◽  
Latency Reversal Agents

While combination antiretroviral therapy maintains undetectable viremia in People Living With HIV (PLWH), a life-long treatment is necessary to prevent viremic rebound after therapy cessation. This rebound seemed mainly caused by long lived HIV-1 latently infected cells reversing to a viral productive status. Reversing latency and elimination of these cells by the so-called shock and kill strategy is one of the main investigated leads to achieve an HIV-1 cure. Small molecules referred as latency reversal agents (LRAs) proved to efficiently reactivate latent CD4 + T cells. However, LRAs impact on de novo infection or HIV-1 production in productively infected macrophages remain elusive. Nontoxic doses of bryostatin-1, JQ1 and romidepsin were investigated in human monocyte-derived macrophages (MDMs). Treatment with bryostatin-1 or romidepsin resulted in a downregulation of CD4 and CCR5 receptors respectively, accompanied by a reduction of R5 tropic virus infection. HIV-1 replication was mainly regulated by receptor modulation for bryostatin-1, while romidepsin effect rely on upregulation of SAMHD1 activity. LRA stimulation of chronically infected cells did not enhance neither HIV-1 production nor gene expression. Surprisingly, bryostatin-1 caused a major decrease in viral production. This effect was not viral strain specific but appears to occur only in myeloid cells. Bryostatin-1 treatment of infected MDMs led to decreased amounts of capsid and matrix mature proteins with little to no modulation of precursors. Our observations revealed that bryostatin-1-treated myeloid and CD4 + T cells are responding differently upon HIV-1 infection. Therefore, additional studies are warranted to more fully assess the efficiency of HIV-1 eradicating strategies. Importance HIV-1 persists in a cellular latent form despite therapy that quickly propagates infection upon treatment interruption. Reversing latency would contribute to eradicate these cells, closing a gap to a cure. Macrophages are an acknowledged HIV-1 reservoir during therapy and are suspected to harbor latency establishment in vivo . Yet, the impact of latency reversal agents (LRAs) on HIV-1 infection and viral production in human macrophages is poorly known but nonetheless crucial to probe the safety of this strategy. In this in vitro study, we discovered encouraging anti-replicative features of distinct LRAs in human macrophages. We also described a new viral production inhibition mechanism by protein kinase C agonists which is specific to myeloid cells. This study provides new insights on HIV-1 propagation restriction potentials by LRAs in human macrophages and underline the importance of assessing latency reversal strategy on all HIV-1 targeted cells.

scholarly journals Sublethal Radiation Affects Antigen Processing and Presentation Genes to Enhance Immunogenicity of Cancer Cells

2020 ◽  
Vol 21 (7) ◽  
pp. 2573 ◽  
Author(s):  
Achamaporn Punnanitinont ◽  
Eric D. Kannisto ◽  
Junko Matsuzaki ◽  
Kunle Odunsi ◽  
Sai Yendamuri ◽  
...  
Keyword(s):  
New York ◽  
T Cells ◽  
Cancer Cells ◽  
Cell Lines ◽  
Antigen Processing ◽  
Tumor Antigens ◽  
T Cell Response ◽  
Live Cells ◽  
X Rays ◽  
Antigen Processing And Presentation

While immunotherapy in cancer is designed to stimulate effector T cell response, tumor-associated antigens have to be presented on malignant cells at a sufficient level for recognition of cancer by T cells. Recent studies suggest that radiotherapy enhances the anti-cancer immune response and also improves the efficacy of immunotherapy. To understand the molecular basis of such observations, we examined the effect of ionizing X-rays on tumor antigens and their presentation in a set of nine human cell lines representing cancers of the esophagus, lung, and head and neck. A single dose of 7.5 or 15 Gy radiation enhanced the New York esophageal squamous cell carcinoma 1 (NY-ESO-1) tumor-antigen-mediated recognition of cancer cells by NY-ESO-1-specific CD8+ T cells. Irradiation led to significant enlargement of live cells after four days, and microscopy and flow cytometry revealed multinucleation and polyploidy in the cells because of dysregulated mitosis, which was also revealed in RNA-sequencing-based transcriptome profiles of cells. Transcriptome analyses also showed that while radiation had no universal effect on genes encoding tumor antigens, it upregulated the expression of numerous genes involved in antigen processing and presentation pathways in all cell lines. This effect may explain the immunostimulatory role of cancer radiotherapy.

scholarly journals The nonpolymorphic MHC Qa-1b mediates CD8+ T cell surveillance of antigen-processing defects

2009 ◽  
Vol 207 (1) ◽  
pp. 207-221 ◽  
Author(s):  
Cláudia C. Oliveira ◽  
Peter A. van Veelen ◽  
Bianca Querido ◽  
Arnoud de Ru ◽  
Marjolein Sluijter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Germ Line ◽  
Wide Spectrum ◽  
Cell Subset ◽  
Target Cells ◽  
Peptide Epitopes ◽  
Leader Peptides

The nonclassical major histocompatibility complex (MHC) Qa-1b accommodates monomorphic leader peptides and functions as a ligand for germ line receptors CD94/NKG2, which are expressed by natural killer cells and CD8+ T cells. We here describe that the conserved peptides are replaced by a novel peptide repertoire of surprising diversity as a result of impairments in the antigen-processing pathway. This novel peptide repertoire represents immunogenic neoantigens for CD8+ T cells, as we found that these Qa-1b–restricted T cells dominantly participated in the response to tumors with processing deficiencies. A surprisingly wide spectrum of target cells, irrespective of transformation status, MHC background, or type of processing deficiency, was recognized by this T cell subset, complying with the conserved nature of Qa-1b. Target cell recognition depended on T cell receptor and Qa-1b interaction, and immunization with identified peptide epitopes demonstrated in vivo priming of CD8+ T cells. Our data reveal that Qa-1b, and most likely its human homologue human leukocyte antigen-E, is important for the defense against processing-deficient cells by displacing the monomorphic leader peptides, which relieves the inhibition through CD94/NKG2A on lymphocytes, and by presenting a novel repertoire of immunogenic peptides, which recruits a subset of cytotoxic CD8+ T cells.

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