scholarly journals CD4+ T cell lymphopenia and dysfunction in severe COVID-19 disease is autocrine TNF-α/TNFRI-dependent

2021 ◽  
Author(s):  
Iulia Popescu ◽  
Mark E. Snyder ◽  
Carlo J. Iasella ◽  
Stefanie J. Hannan ◽  
Ritchie Koshy ◽  
...  
Keyword(s):  
T Cell ◽  
Severe Disease ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Infliximab Treatment ◽  
Mild Disease ◽  
Cell Responses ◽  
Activation Induced Cell Death ◽  
Tnf Α

Lymphopenia is common in severe COVID-19 disease, yet the mechanisms are poorly understood. In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared to recovered, mild disease (p<0.0001). In severe disease, immunodominant CD4+ T cell responses to Spike-1(S1) produced increased in vitro TNF-α, but impaired proliferation and increased susceptibility to activation-induced cell death (AICD). CD4+TNF-α+ T cell responses inversely correlated with absolute CD4+ counts from severe COVID-19 patients (n=76; R=-0.744, P<0.0001). TNF-α blockade including infliximab or anti-TNFRI antibodies strikingly rescued S1-specific CD4+ proliferation and abrogated S1-AICD in severe COVID-19 patients (P<0.001). Single-cell RNAseq demonstrated downregulation of Type-1 cytokines and NFκB signaling in S1-stimulated CD4+ cells with infliximab treatment. Lung CD4+ T cells in severe COVID-19 were reduced and produced higher TNF-α versus PBMC. Together, our findings show COVID-19-associated CD4+ lymphopenia and dysfunction is autocrine TNF-α/TNFRI-dependent and therapies targeting TNF-α may be beneficial in severe COVID-19.

scholarly journals Deciphering the Mechanisms of Improved Immunogenicity of Hypochlorous Acid-Treated Antigens in Anti-Cancer Dendritic Cell-Based Vaccines

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 271
Author(s):  
Michele Graciotti ◽  
Fabio Marino ◽  
HuiSong Pak ◽  
Petra Baumgaertner ◽  
Anne-Christine Thierry ◽  
...  
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
Hypochlorous Acid ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Tumor Lysate ◽  
Cell Responses ◽  
Significant Difference

Hypochlorous acid (HOCl)-treated whole tumor cell lysates (Ox-L) have been shown to be more immunogenic when used as an antigen source for therapeutic dendritic cell (DC)-based vaccines, improving downstream immune responses both in vitro and in vivo. However, the mechanisms behind the improved immunogenicity are still elusive. To address this question, we conducted a proteomic and immunopeptidomics analyses to map modifications and alterations introduced by HOCl treatment using a human melanoma cell line as a model system. First, we show that one-hour HOCl incubation readily induces extensive protein oxidation, mitochondrial biogenesis, and increased expression of chaperones and antioxidant proteins, all features indicative of an activation of oxidative stress-response pathways. Characterization of the DC proteome after loading with HOCl treated tumor lysate (Ox-L) showed no significant difference compared to loading with untreated whole tumor lysate (FT-L). On the other hand, detailed immunopeptidomic analyses on monocyte-derived DCs (mo-DCs) revealed a great increase in human leukocyte antigen class II (HLA-II) presentation in mo-DCs loaded with Ox-L compared to the FT-L control. Further, 2026 HLA-II ligands uniquely presented on Ox-L-loaded mo-DCs were identified. In comparison, identities and intensities of HLA class I (HLA-I) ligands were overall comparable. We found that HLA-II ligands uniquely presented by DCs loaded with Ox-L were more solvent exposed in the structures of their source proteins, contrary to what has been hypothesized so far. Analyses from a phase I clinical trial showed that vaccinating patients using autologous Ox-L as an antigen source efficiently induces polyfunctional vaccine-specific CD4+ T cell responses. Hence, these results suggest that the increased immunogenicity of Ox-L is, at least in part, due to qualitative and quantitative changes in the HLA-II ligandome, potentially leading to an increased HLA-II dependent stimulation of the T cell compartment (i.e., CD4+ T cell responses). These results further contribute to the development of more effective and immunogenic DC-based vaccines and to the molecular understanding of the mechanism behind HOCl adjuvant properties.

Polarized Type-1 Dendritic Cells (DC1) Producing High Levels of IL-12 Family Members Rescue Patient TH1-type Antimelanoma CD4+ T cell Responses In Vitro

2007 ◽  
Vol 30 (1) ◽  
pp. 75-82 ◽  
Author(s):  
Amy Wesa ◽  
Pawel Kalinski ◽  
John M. Kirkwood ◽  
Tomohide Tatsumi ◽  
Walter J. Storkus
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Family Members ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Cell Responses

scholarly journals Broadly directed SARS-CoV-2-specific CD4+ T cell response includes frequently detected peptide specificities within the membrane and nucleoprotein in patients with acute and resolved COVID-19

2021 ◽  
Vol 17 (9) ◽  
pp. e1009842
Author(s):  
Janna Heide ◽  
Sophia Schulte ◽  
Matin Kohsar ◽  
Thomas Theo Brehm ◽  
Marissa Herrmann ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Ex Vivo ◽  
Intracellular Cytokine Staining ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Single Peptide

The aim of this study was to define the breadth and specificity of dominant SARS-CoV-2-specific T cell epitopes using a comprehensive set of 135 overlapping 15-mer peptides covering the SARS-CoV-2 envelope (E), membrane (M) and nucleoprotein (N) in a cohort of 34 individuals with acute (n = 10) and resolved (n = 24) COVID-19. Following short-term virus-specific in vitro cultivation, the single peptide-specific CD4+ T cell response of each patient was screened using enzyme linked immuno spot assay (ELISpot) and confirmed by single-peptide intracellular cytokine staining (ICS) for interferon-γ (IFN-γ) production. 97% (n = 33) of patients elicited one or more N, M or E-specific CD4+ T cell responses and each patient targeted on average 21.7 (range 0–79) peptide specificities. Overall, we identified 10 N, M or E-specific peptides that showed a response frequency of more than 36% and five of them showed high binding affinity to multiple HLA class II binders in subsequent in vitro HLA binding assays. Three peptides elicited CD4+ T cell responses in more than 55% of all patients, namely Mem_P30 (aa146-160), Mem_P36 (aa176-190), both located within the M protein, and Ncl_P18 (aa86-100) located within the N protein. These peptides were further defined in terms of length and HLA restriction. Based on this epitope and restriction data we developed a novel DRB*11 tetramer (Mem_aa145-164) and examined the ex vivo phenotype of SARS-CoV-2-specific CD4+ T cells in one patient. This detailed characterization of single T cell peptide responses demonstrates that SARS-CoV-2 infection universally primes a broad T cell response directed against multiple specificities located within the N, M and E structural protein.

scholarly journals Dominant TNF-α+ Mycobacterium tuberculosis–specific CD4+ T cell responses discriminate between latent infection and active disease

2011 ◽  
Vol 17 (3) ◽  
pp. 372-376 ◽  
Author(s):  
Alexandre Harari ◽  
Virginie Rozot ◽  
Felicitas Bellutti Enders ◽  
Matthieu Perreau ◽  
Jesica Mazza Stalder ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Latent Infection ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Tnf Α ◽  
Active Disease

Presentation of proteins encapsulated in sterically stabilized liposomes by dendritic cells initiates CD8+ T-cell responses in vivo

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3505-3513 ◽  
Author(s):  
Ralf Ignatius ◽  
Karsten Mahnke ◽  
Miguel Rivera ◽  
Keelung Hong ◽  
Frank Isdell ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Soluble Protein ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Sterically Stabilized Liposomes

Liposomes have been proposed as a vehicle to deliver proteins to antigen-presenting cells (APC), such as dendritic cells (DC), to stimulate strong T cell–mediated immune responses. Unfortunately, because of their instability in vivo and their rapid uptake by cells of the mononuclear phagocyte system on intravenous administration, most types of conventional liposomes lack clinical applicability. In contrast, sterically stabilized liposomes (SL) have increased in vivo stability. It is shown that both immature and mature DC take up SL into neutral or mildly acidic compartments distinct from endocytic vacuoles. These DC presented SL-encapsulated protein to both CD4+ and CD8+ T cells in vitro. Although CD4+ T-cell responses were comparable to those induced by soluble protein, CD8+ T-cell proliferation was up to 300-fold stronger when DC had been pulsed with SL-encapsulated ovalbumin. DC processed SL-encapsulated antigen through a TAP-dependent mechanism. Immunization of mice with SL-encapsulated ovalbumin led to antigen presentation by DC in vivo and stimulated greater CD8+ T-cell responses than immunization with soluble protein or with conventional or positively charged liposomes carrying ovalbumin. Therefore, the application of SL-encapsulated antigens offers a novel effective, safe vaccine approach if a combination of CD8+and CD4+ T-cell responses is desired (ie, in anti-viral or anti-tumor immunity).

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