scholarly journals Identification of a Promiscuous Conserved CTL Epitope Within the SARS-CoV-2 Spike Protein

2021 ◽  
Author(s):  
Sheng Jiang ◽  
Shuting Wu ◽  
Gan Zhao ◽  
Yue He ◽  
Xinrong Guo ◽  
...  
Keyword(s):  
T Cell ◽  
Cellular Response ◽  
Spike Protein ◽  
Target Antigen ◽  
T Cell Epitopes ◽  
Global Public Health ◽  
Mhc I ◽  
Mhc Ii ◽  
Ctl Epitope ◽  
Infected Cells

Abstract The COVID-19 disease caused by infection with SARS-CoV-2 and its variants is devastating to the global public health and economy. To date, over a hundred COVID-19 vaccines are known to be under development and the few that have been approved to fight the disease are using the spike protein as the primary target antigen. Although virus neutralizing epitopes are mainly located within the RBD of the spike protein, the presence of T cell epitopes, particularly the CTL epitopes that are likely to be needed for killing infected cells, has received comparatively little attention. In this study, we predicted several potential T cell epitopes with web-based analytic tools, and narrowed them down from several potential MHC‑I and MHC‑II epitopes by ELIspot and cytolytic assays to a conserved MHC‑I epitope. The epitope is highly conserved in current viral variants and compatible with presentation by most HLA alleles worldwide. In conclusion, we identified a CTL epitope suitable for evaluating the CD8+ T cell-mediated cellular response and potentially for addition into future COVID-19 vaccine candidates to maximize CTL responses against SARS-CoV-2.

scholarly journals Identification of a promiscuous conserved CTL epitope within the SARS-CoV-2 spike protein

2021 ◽  
Author(s):  
Sheng Jiang ◽  
Shuting Wu ◽  
Gan Zhao ◽  
Yue He ◽  
Xinrong Guo ◽  
...  
Keyword(s):  
T Cell ◽  
Cellular Response ◽  
Spike Protein ◽  
Target Antigen ◽  
T Cell Epitopes ◽  
Global Public Health ◽  
Mhc I ◽  
Mhc Ii ◽  
Ctl Epitope ◽  
Infected Cells

The COVID-19 disease caused by infection with SARS-CoV-2 and its variants is devastating to the global public health and economy. To date, over a hundred COVID-19 vaccines are known to be under development and the few that have been approved to fight the disease are using the spike protein as the primary target antigen. Although virus neutralizing epitopes are mainly located within the RBD of the spike protein, the presence of T cell epitopes, particularly the CTL epitopes that are likely to be needed for killing infected cells, has received comparatively little attention. In this study, we predicted several potential T cell epitopes with web-based analytic tools, and narrowed them down from several potential MHC I and MHC II epitopes by ELIspot and cytolytic assays to a conserved MHC I epitope. The epitope is highly conserved in current viral variants and compatible with presentation by most HLA alleles worldwide. In conclusion, we identified a CTL epitope suitable for evaluating the CD8+ T cell-mediated cellular response and potentially for addition into future COVID-19 vaccine candidates to maximize CTL responses against SARS-CoV-2.

scholarly journals Pol-Specific CD8+ T Cells Recognize Simian Immunodeficiency Virus-Infected Cells Prior to Nef-Mediated Major Histocompatibility Complex Class I Downregulation

2007 ◽  
Vol 81 (21) ◽  
pp. 11703-11712 ◽  
Author(s):  
Jonah B. Sacha ◽  
Chungwon Chung ◽  
Jason Reed ◽  
Anna K. Jonas ◽  
Alexander T. Bean ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Major Histocompatibility Complex Class ◽  
T Cell Epitopes ◽  
Complex Class ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Infected Cells

ABSTRACT Effective, vaccine-induced CD8+ T-cell responses should recognize infected cells early enough to prevent production of progeny virions. We have recently shown that Gag-specific CD8+ T cells recognize simian immunodeficiency virus-infected cells at 2 h postinfection, whereas Env-specific CD8+ T cells do not recognize infected cells until much later in infection. However, it remains unknown when other proteins present in the viral particle are presented to CD8+ T cells after infection. To address this issue, we explored CD8+ T-cell recognition of epitopes derived from two other relatively large virion proteins, Pol and Nef. Surprisingly, infected cells efficiently presented CD8+ T-cell epitopes from virion-derived Pol proteins within 2 h of infection. In contrast, Nef-specific CD8+ T cells did not recognize infected cells until 12 h postinfection. Additionally, we show that SIVmac239 Nef downregulated surface major histocompatibility complex class I (MHC-I) molecules beginning at 12 h postinfection, concomitant with presentation of Nef-derived CD8+ T-cell epitopes. Finally, Pol-specific CD8+ T cells eliminated infected cells as early as 6 h postinfection, well before MHC-I downregulation, suggesting a previously underappreciated antiviral role for Pol-specific CD8+ T cells.

scholarly journals Hepatitis B Virus Covalently Closed Circular DNA Interacting HBx and HBc Proteins Global Conservancy Analysis and Related B or T lymphocyte Epitopes

2021 ◽  
Author(s):  
Umar Saeed ◽  
Zahra Zahid Piracha ◽  
Rizwan Uppal
Keyword(s):  
Hepatitis B Virus ◽  
T Cell ◽  
T Cell Epitopes ◽  
Mhc I ◽  
Circular Dna ◽  
Consensus Sequences ◽  
Global Consensus ◽  
Mhc Ii ◽  
Hbv Genotypes ◽  
B Virus

Abstract Background:The Hepatitis B Virus HBx and HBc proteins associate with covalently closed circular DNA, which is the main reason for intrahepatic viral persistence and major cause due to which HBV cure has not been achieved yet. The aims of present study were to generate HBV genotype-specific consensus sequences of HBx and HBc, align all ten (A to J) consensus sequences to develop global consensus sequences of HBx and HBc, analyze variable and conserved motifs, and to predict highly conserved B and T cell binding epitopes in HBx and HBc proteins, respectively.Methods:237 HBx and 207 HBc sequences, belonging to all HBV genotypes reported globally, were aligned in CLC main workbench to draw global consensus sequences and phylogenetic analysis was performed. The location of possible B cell epitopes were analyzed using immune Epitope Database (IEDB), while possible T cell epitopes were analyzed using ProPred-I and ProPred in-silico prediction tools. Results:The HBx residues 52H to 59P, which are important for augmentation effect in HBV replication and 137C, which is crucial for transactivation of HBx are conserved in all HBV genotypes. The HBc residues 141S to149V, which are crucial for pre-genomic RNA packaging, viral DNA synthesis and virion secretion are highly conserved across all the genotypes of HBV. The HBx related epitopes X-B2 and X-B4, and HBc related C-B6 and C-B7 epitopes could be important candidates for B-cell based vaccine. Among HBx related MHC-I epitopes X-M2, X-M5, X-M8, X-M11, X-M12, X-M20, X-M22, X-M25, X-M27 and X-M32, and MHC-II epitopes the X-T4, X-T6 and X-T8 could be important targets for vaccine development. While among HBc related MHC-I epitopes C-M1, C-M2, C-M4, C-M6-11, C-M13, C-M19, C-M24-26, C-M30, C-M34-36, C-M40 and C-M43-45, and MHC-II epitopes the C-T1-3, C-T9, C-T10, C-T12, C-T14 and C-T16-18 epitopes could be ideal epitopes with high conservancy across all HBV genotypes. Conclusion:The analysis will aid in screening of novel anti-HBV agents and designing of site-specific inhibitors which may show response against all genotypes. Also the predicted B- or T cell epitopes might be effective for designing antibodies against all majorly occurring genotypes of HBV across the world.

Self-Peptide Recognition of Posterior Eye Segment Epitopes Mediated By Allogeneic T Cells in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1173-1173
Author(s):  
Nora Mirza ◽  
Manfred Zierhut ◽  
Andreas Korn ◽  
Antje Bornemann ◽  
Christoph Simon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Epitopes ◽  
Healthy Individuals ◽  
Cell Reactivity ◽  
Mhc I ◽  
Mhc Ii ◽  
T Cell Reactivity ◽  
Self Antigens

Abstract Graft versus Host Disease (GvHD) is the major complication of allogeneic hematopoetic cell transplantation (HCT). It mostly affects the gastrointestinal tract, skin or liver, but may also involve the central nervous system (CNS). Although GvHD is believed to be mainly mediated by T cells recognizing HLA mismatches or minor histocompatibility antigens (MHC-restricted peptides differing in single amino acids based on protein sequence variants between donor and recipient due to genetic differences), limited evidence is known about the exact MHC-restricted T cell epitopes recognized on recipient cells. In this study, we evaluated the clinical manifestation of GvHD in the posterior eye segment (PS) as part of the CNS and characterized self-antigens mediating reactivity of allogeneic T cells. The first patient group comprised 6 individuals (3 women and 3 men, median age 40 years, range 20-58 years) with diseases of the PS after HCT. Diseases were ALL (n=4), AML (n=1) and MPS (n=1). 8 transplantations (1-2 per patient) were performed using grafts from matched related (MRD, n=1), matched unrelated (MUD, n=4), mismatched unrelated (MMUD, n=2) or haploidentical (n=1) donors. The second group included 22 patients (7 women and 15 men, median age 55 years, range 29-69 years) irrespective of ocular symptoms recruited before HCT. Diseases were AML (n=7), CML (n=1), MDS (n=4), MPS (n=5), multiple myeloma (n=1) and lymphoma (n=4). All patients received grafts from HLA-identical donors (MRD n=7, MUD n=15). GvHD prophylaxis was performed using standard protocols. Peripheral blood mononuclear cells (PBMC) and DNA were isolated from blood samples. Autologous cell samples were blood samples before or oral mucosa after HCT. Allogeneic cells were obtained from patients with complete donor chimerism. DNA sequencing was performed to identify donor-recipient single nucleotide polymorphisms (SNP). Retina specific candidate epitopes derived from the retinal guanylate cyclase 2D (GUCY2D), the retinoid binding protein (RBP) and the guanylate cyclase activating proteins A1 und B1 (GUCA1A/GUCA1B) were predicted based on known SNP and individual protein sequences using the database EpiToolKit. PBMC were prestimulated with both wildtype and SNP peptides. T cell reactivity was determined in ELISpot and intracellular cytokine staining. Moreover, T cells from 5 family donors were evaluated. All epitopes were evaluated in at least 8 healthy individuals carrying the respective HLA-subtype. Immunogenicity of MHC-I restricted candidate epitopes was determined in in vitro priming. PS diagnoses were optical atrophy (n=2), in 1 case combined with a selective dysfunction of the cones, optic neuritis (n=2), anemic retinopathy (n=1) and VZV retinitis (n=1). In two of these patients (one with selective cone dystrophy, the other with VZV retinitis) antigen specific T cells against MHC-II restricted GUCY2D epitopes could be detected 24 and 40 months after HCT. DNA sequencing did not reveal a SNP indicating recognition of self-antigens. In 6/22 patients without PS symptoms, retina-specific T cells could be detected, here directed against MHC-II restricted epitopes derived from GUCA1A (n=3), GUCA1B (n=3) and GUCY2D (n=3) between 4 and 14 months after HCT. After stimulation with the variant peptide, no T cell reactivity occurred, confirming that the observed responses were sequence specific. T cell responses tended to increase over time but could disappear at certain time points. Again, no SNP could be observed. Hence, T cell reactivity was directed against self-epitopes. Transplantation of retina-antigen specific cells and cross-reactivity against naturally occurring epitopes were excluded since no reactivity could be detected in donor samples and healthy individuals. In in vitro priming experiments, 36/55 of MHC-I restricted peptides could be confirmed as T cell epitopes. Thus, GvHD manifestations of the retina can be detected in patients after allogeneic HCT and can be mediated by antigen-specific T cells. Development of PS GvHD may be triggered by viral infections and should be considered in case of atypical ophthalmologic findings. The antigens recognized hereby can be self-antigens and do not need to be based on genetic differences between donor and recipient. In summary, recognition of self-antigens by allogeneic T cells represents a novel pathomechanism of graft-host-interaction in patients undergoing allogeneic HCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Scouting the Receptor Binding Domain of COVID-19: A Comprehensive Immunoinformatics Inquisition

2020 ◽  
Author(s):  
Zaira Rehman ◽  
Ammad Fahim ◽  
Muhammad Faraz Bhatti
Keyword(s):  
T Cell ◽  
Receptor Binding ◽  
Binding Domain ◽  
Peptide Sequence ◽  
Preventive Strategy ◽  
Receptor Binding Domain ◽  
T Cell Epitopes ◽  
Mhc I ◽  
Mhc Ii ◽  
Potential Vaccine

Abstract The December of 2019 witnessed emergence of worldwide outbreak by a novel strain of coronavirus termed COVID-19 with sequence similarity of overall 96.2% with BatCoV RaTG13 (coronavirus isolated from bat) and 94% sequence identity with Severe Acute respiratory syndrome Virus (SARS-CoV) that resulted in outbreak in 2002-2003. There is no therapeutic or preventive strategy like vaccine developed so far to overcome infection.The receptor binding domain (RBD) of COVID-19 for any potential vaccine epitopes were explored. The structure of RBD of COVID-19, BatCoV RaTG13 and bACE2 were chalked through homology modeling followed by molecular docking and structural validation. A comprehensive immunoinformatics approach mapped conserved peptide sequence on COVID-19 RBD for their B-, Helper T- & Cytotoxic T-cell epitope profile. The recognized epitopes were further studied and validated for their docking interaction with MHC-I and MHC-II alleles. Through immune-informatics approaches the study identified conserved B- and T-cell epitopes in RBD. The B-cell epitopes lying within the receptor binding motif, LFRKSN and SYGFQPT l were found to be highly antigenic. Among T-cell epitopes, the epitope CVADYSVLY and FTNVYADSF were antigenic and exhibited affinity for maximum number of MHC-I alleles. The T cell epitopes YRLFRKSNL, VYAWNRKRI displayed affinity for maximum number of MHC-II alleles. The docking analysis of the epitopes with MHC proteins revealed strong interactions of T-cell epitopes with MHC-I and MHC-II alleles. The overlapping epitope among B- and T-cells was YRLFRKSNL. The deployment of these epitopes in potential vaccine against COVID-19 may help in sweeping the COVID-19 infectious spread.

scholarly journals High Levels of a Major Histocompatibility Complex II–Self Peptide Complex on Dendritic Cells from the T Cell Areas of Lymph Nodes

1997 ◽  
Vol 186 (5) ◽  
pp. 665-672 ◽  
Author(s):  
Kayo Inaba ◽  
Maggie Pack ◽  
Muneo Inaba ◽  
Hiraki Sakuta ◽  
Frank Isdell ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Mhc I ◽  
Peptide Complex ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Peripheral Lymph ◽  
Free Media ◽  
Very High

T lymphocytes recirculate continually through the T cell areas of peripheral lymph nodes. During each passage, the T cells survey the surface of large dendritic cells (DCs), also known as interdigitating cells. However, these DCs have been difficult to release from the lymph node. By emphasizing the use of calcium-free media, as shown by Vremec et al. (Vremec, D., M. Zorbas, R. Scollay, D.J. Saunders, C.F. Ardavin, L. Wu, and K. Shortman. 1992. J. Exp. Med. 176:47–58.), we have been able to release and enrich DCs from the T cell areas. The DCs express the CD11c leukocyte integrin, the DEC-205 multilectin receptor for antigen presentation, the intracellular granule antigens which are recognized by monoclonal antibodies M342, 2A1, and MIDC-8, very high levels of MHC I and MHC II, and abundant accessory molecules such as CD40, CD54, and CD86. When examined with the Y-Ae monoclonal which recognizes complexes formed between I-Ab and a peptide derived from I-Eα, the T cell area DCs expressed the highest levels. The enriched DCs also stimulated a T-T hybridoma specific for this MHC II–peptide complex, and the hybridoma underwent apoptosis. Therefore DCs within the T cell areas can be isolated. Because they present very high levels of self peptides, these DCs should be considered in the regulation of self reactivity in the periphery.

scholarly journals A Novel Tuberculosis DNA Vaccine in an HIV-1 p24 Protein Backbone Confers Protection against Mycobacterium tuberculosis and Simultaneously Elicits Robust Humoral and Cellular Responses to HIV-1

2012 ◽  
Vol 19 (5) ◽  
pp. 723-730 ◽  
Author(s):  
Xiaoman Li ◽  
Wei Xu ◽  
Sidong Xiong
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Dna Vaccine ◽  
Cellular Response ◽  
Mycobacterial Infection ◽  
T Cell Epitopes ◽  
Content Type ◽  
P24 Protein ◽  
Elevated Frequency ◽  
Hiv 1

ABSTRACTTuberculosis (TB) caused byMycobacterium tuberculosisremains a major infectious disease worldwide. Moreover, latentM. tuberculosisinfection is more likely to progress to active TB and eventually leads to death when HIV infection is involved. Thus, it is urgent to develop a novel TB vaccine with immunogenicity to bothM. tuberculosisand HIV. In this study, four uncharacterized T cell epitopes from MPT64, Ag85A, Ag85B, and TB10.4 antigens ofM. tuberculosiswere predicted, and HIV-1-derived p24, an immunodominant protein that can induce protective responses to HIV-1, was used as an immunogenic backbone.M. tuberculosisepitopes were incorporated separately into the gene backbone of p24, forming a pP24-Mtb DNA vaccine. We demonstrated that pP24-Mtb immunization induced a strongM. tuberculosis-specific cellular response as evidenced by T cell proliferation, cytotoxicity, and elevated frequency of gamma interferon (IFN-γ)-secreting T cells. Interestingly, a p24-specific cellular response and high levels of p24-specific IgG were also induced by pP24-Mtb immunization. When the protective effect was assessed after mycobacterial challenge, pP24-Mtb vaccination significantly reduced tissue bacterial loads and profoundly attenuated the mycobacterial infection-related lung inflammation and injury. Our findings demonstrated that the pP24-Mtb tuberculosis vaccine confers effective protection against mycobacterial challenge with simultaneously elicited robust immune responses to HIV-1, which may provide clues for developing novel vaccines to prevent dual infections.

scholarly journals Why Are CD8 T Cell Epitopes of Human Influenza A Virus Conserved?

2018 ◽  
Author(s):  
Zheng-Rong Tiger Li ◽  
Veronika I. Zarnitsyna ◽  
Anice C. Lowen ◽  
Daniel Weissman ◽  
Katia Koelle ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza A Virus ◽  
Influenza A ◽  
Cd8 T Cell ◽  
Influenza Vaccines ◽  
T Cell Epitopes ◽  
Word Count ◽  
Mhc I ◽  
Escape Variant ◽  
Replicative Fitness

AbstractThe high-degree conservation of CD8 T cell epitopes of influenza A virus (IAV) may allow T cell-inducing vaccines effective across different strains and subtypes. This conservation is not fully explained by functional constraint, since additional mutation(s) can compensate the replicative fitness loss of IAV escape-variant. Here, we propose three additional mechanisms that contribute to the conservation of CD8 T cell epitopes of IAV. First, influenza-specific CD8 T cells may protect predominantly against severe pathology rather than infection and may only have a modest effect on transmission. Second, polymorphism of human MHC-I gene restricts the advantage of an escape-variant to only a small fraction of human population, who carry the relevant MHC-I alleles. Finally, infection with CD8 T cell-escapevariants may result in compensatory increase in the responses to other epitopes of IAV. A combination of population genetics and epidemiological models is used to examine how the interplay between these mechanisms affects the rate of invasion of IAV escape-variants. We conclude that the invasion of an escape-variant will be very slow with a timescale of decades or longer, even if the escape-variant does not have a replicative fitness loss. Our results suggest T cell-inducing vaccines may not engender the rapid evolution of IAV and serve as a foundation for future modeling works on the long-term effectiveness and impacts of T cell-inducing influenza vaccines. (Word count: 221)ImportanceUniversal influenza vaccines against the conserved epitopes of influenza A virus have been proposed to minimize the burden of seasonal outbreaks and prepare for the pandemics. However, it is not clear to which extent the T cell-inducing vaccines will select for viruses that escape the T cell responses. Our mathematical models suggest how the nature of CD8 T cell protection contributes to the conservation of the CD8 T cell epitopes of influenza A virus. Also, it points out the essential biological parameters and questions that need addressing by future experimental works. (Word count: 91)

scholarly journals The critical role of CD4+ T cells in PD-1 blockade against MHC-II–expressing tumors such as classic Hodgkin lymphoma

2020 ◽  
Vol 4 (17) ◽  
pp. 4069-4082
Author(s):  
Joji Nagasaki ◽  
Yosuke Togashi ◽  
Takeaki Sugawara ◽  
Makiko Itami ◽  
Nobuhiko Yamauchi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Cd4 T Cell ◽  
Antitumor Effects ◽  
Cell Axis ◽  
Mhc I ◽  
Mhc Ii

Abstract Classic Hodgkin lymphoma (cHL) responds markedly to PD-1 blockade therapy, and the clinical responses are reportedly dependent on expression of major histocompatibility complex class II (MHC-II). This dependence is different from other solid tumors, in which the MHC class I (MHC-I)/CD8+ T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II/CD4+ T-cell axis in the antitumor effect of PD-1 blockade on cHL. In cHL, MHC-I expression was frequently lost, but MHC-II expression was maintained. CD4+ T cells highly infiltrated the tumor microenvironment of MHC-II–expressing cHL, regardless of MHC-I expression status. Consequently, CD4+ T-cell, but not CD8+ T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II–expressing cHL associated with CD4+ T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD4+ T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I−MHC-II+ tumors but not on MHC-I−MHC-II− tumors, in a cytotoxic CD4+ T-cell–dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD4+ T cells in MHC-II–expressing tumors. Therefore, the combination of LAG-3 blockade with PD-1 blockade showed a far stronger antitumor immunity compared with either treatment alone. We propose that PD-1 blockade therapies have antitumor effects on MHC-II–expressing tumors such as cHL that are mediated by cytotoxic CD4+ T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.

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