Protective T Cell Responses Featured by Concordant Recognition of Middle East Respiratory Syndrome Coronavirus–Derived CD8+ T Cell Epitopes and Host MHC

ABSTRACTAlthough parasite strain-restricted CD8 T cell responses have been described for several protozoa, the precise role of antigenic variability in immunity is poorly understood. The tick-borne protozoan parasiteTheileria annulatainfects leukocytes and causes an acute, often fatal lymphoproliferative disease in cattle. Building on previous evidence of strain-restricted CD8 T cell responses toT. annulata, this study set out to identify and characterize the variability of the target antigens. Three antigens were identified by screening expressed parasite cDNAs with specific CD8 T cell lines. In cattle expressing the A10 class I major histocompatibility complex haplotype, A10-restricted CD8 T cell responses were shown to be focused entirely on a single dominant epitope in one of these antigens (Ta9). Sequencing of the Ta9 gene from field isolates ofT. annulatademonstrated extensive sequence divergence, resulting in amino acid polymorphism within the A10-restricted epitope and a second A14-restricted epitope. Statistical analysis of the allelic sequences revealed evidence of positive selection for amino acid substitutions within the region encoding the CD8 T cell epitopes. Sequence differences in the A10-restricted epitope were shown to result in differential recognition by individual CD8 T cell clones, while clones also differed in their ability to recognize different alleles. Moreover, the representation of these clonal specificities within the responding CD8 T cell populations differed between animals. As well as providing an explanation for incomplete protection observed after heterologous parasite challenge of vaccinated cattle, these results have important implications for the choice of antigens for the development of novel subunit vaccines.

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Protection against Vaccinia Virus Challenge by CD8 Memory T Cells Resolved by Molecular Mimicry

Journal of Virology ◽

10.1128/jvi.01280-06 ◽

2006 ◽

Vol 81 (2) ◽

pp. 934-944 ◽

Cited By ~ 28

Author(s):

Markus Cornberg ◽

Brian S. Sheridan ◽

Frances M. Saccoccio ◽

Michael A. Brehm ◽

Liisa K. Selin

Keyword(s):

T Cells ◽

T Cell ◽

Vaccinia Virus ◽

Cd8 T Cells ◽

Protective Immunity ◽

Molecular Mimicry ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Epitopes ◽

Cell Responses

ABSTRACT Live vaccinia virus (VV) vaccination has been highly successful in eradicating smallpox. However, the mechanisms of immunity involved in mediating this protective effect are still poorly understood, and the roles of CD8 T-cell responses in primary and secondary VV infections are not clearly identified. By applying the concept of molecular mimicry to identify potential CD8 T-cell epitopes that stimulate cross-reactive T cells specific to lymphocytic choriomeningitis virus (LCMV) and VV, we identified after screening only 115 peptides two VV-specific immunogenic epitopes that mediated protective immunity against VV. An immunodominant epitope, VV-e7r130, did not generate cross-reactive T-cell responses to LCMV, and a subdominant epitope, VV-a11r198, did generate cross-reactive responses to LCMV. Infection with VV induced strong epitope-specific responses which were stable into long-term memory and peaked at the time virus was cleared, consistent with CD8 T cells assisting in the control of VV. Two different approaches, direct adoptive transfer of VV-e7r-specific CD8 T cells and prior immunization with a VV-e7r-expressing ubiquitinated minigene, demonstrated that memory CD8 T cells alone could play a significant role in protective immunity against VV. These studies suggest that exploiting cross-reactive responses between viruses may be a useful tool to complement existing technology in predicting immunogenic epitopes to large viruses, such as VV, leading to a better understanding of the role CD8 T cells play during these viral infections.

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Public T-cell epitopes shared among SARS-CoV-2 variants are presented on prevalent HLA class I alleles

10.1101/2021.10.13.463911 ◽

2021 ◽

Author(s):

Saskia Meyer ◽

Isaac Blaas ◽

Ravi Chand Bollineni ◽

Marina Delic-Sarac ◽

Trung T Tran ◽

...

Keyword(s):

T Cell ◽

Cell Response ◽

T Cell Responses ◽

Hla Class I ◽

Cd8 T Cell ◽

T Cell Response ◽

Class I ◽

T Cell Epitopes ◽

Low Frequencies ◽

Cell Responses

T-cell epitopes with broad population coverage may form the basis for a new generation of SARS-CoV-2 vaccines. However, published studies on immunoprevalence are limited by small test cohorts, low frequencies of antigen-specific cells and lack of data correlating eluted HLA ligands with T-cell responsiveness. Here, we investigate CD8 T-cell responses to 48 peptides eluted from prevalent HLA alleles, and an additional 84 predicted binders, in a large cohort of convalescents (n=83) and pre-pandemic control samples (n=19). We identify nine conserved SARS-CoV-2 specific epitopes restricted by four of the most prevalent HLA class I alleles in Caucasians, to which responding CD8 T cells are detected in 70-100% of convalescents expressing the relevant HLA allele, including two novel epitopes. We find a strong correlation between immunoprevalence and immunodominance. Using a new algorithm, we predict that a vaccine including these epitopes would induce a T cell response in 83% of Caucasians. Significance Statement: Vaccines that induce broad T-cell responses may boost immunity as protection from current vaccines against SARS-CoV-2 is waning. From a manufacturing standpoint, and to deliver the highest possible dose of the most immunogenic antigens, it is rational to limit the number of epitopes to those inducing the strongest immune responses in the highest proportion of individuals in a population. Our data show that the CD8 T cell response to SARS-CoV-2 is more focused than previously believed. We identify nine conserved SARS-CoV-2 specific CD8 T cell epitopes restricted by four of the most prevalent HLA class I alleles in Caucasians and demonstrate that seven of these are endogenously presented.

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Negligible impact of SARS-CoV-2 variants on CD4+ and CD8+ T cell reactivity in COVID-19 exposed donors and vaccinees.

10.1101/2021.02.27.433180 ◽

2021 ◽

Author(s):

Alison Tarke ◽

John Sidney ◽

Nils Methot ◽

Yun Zhang ◽

Jennifer M Dan ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Cd8 T Cell ◽

Comprehensive Analysis ◽

T Cell Epitopes ◽

Cell Reactivity ◽

Cell Responses ◽

Adaptive Immune ◽

T Cell Reactivity

The emergence of SARS-CoV-2 variants highlighted the need to better understand adaptive immune responses to this virus. It is important to address whether also CD4+ and CD8+ T cell responses are affected, because of the role they play in disease resolution and modulation of COVID-19 disease severity. Here we performed a comprehensive analysis of SARS-CoV-2-specific CD4+ and CD8+ T cell responses from COVID-19 convalescent subjects recognizing the ancestral strain, compared to variant lineages B.1.1.7, B.1.351, P.1, and CAL.20C as well as recipients of the Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) COVID-19 vaccines. Similarly, we demonstrate that the sequences of the vast majority of SARS-CoV-2 T cell epitopes are not affected by the mutations found in the variants analyzed. Overall, the results demonstrate that CD4+ and CD8+ T cell responses in convalescent COVID-19 subjects or COVID-19 mRNA vaccinees are not substantially affected by mutations found in the SARS-CoV-2 variants.

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Potent HIV-1-Specific CD8 T Cell Responses Induced in Mice after Priming with a Multiepitopic DNA-TMEP and Boosting with the HIV Vaccine MVA-B

Viruses ◽

10.3390/v10080424 ◽

2018 ◽

Vol 10 (8) ◽

pp. 424 ◽

Cited By ~ 5

Author(s):

Beatriz Perdiguero ◽

Suresh C. Raman ◽

Cristina Sánchez-Corzo ◽

Carlos Oscar S. Sorzano ◽

José Ramón Valverde ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Effective Vaccine ◽

T Cell Epitopes ◽

Cell Responses ◽

Modified Vaccinia Virus Ankara ◽

Hiv 1

An effective vaccine against Human Immunodeficiency Virus (HIV) still remains the best solution to provide a sustainable control and/or eradication of the virus. We have previously generated the HIV-1 vaccine modified vaccinia virus Ankara (MVA)-B, which exhibited good immunogenicity profile in phase I prophylactic and therapeutic clinical trials, but was unable to prevent viral rebound after antiretroviral (ART) removal. To potentiate the immunogenicity of MVA-B, here we described the design and immune responses elicited in mice by a new T cell multi-epitopic B (TMEP-B) immunogen, vectored by DNA, when administered in homologous or heterologous prime/boost regimens in combination with MVA-B. The TMEP-B protein contained conserved regions from Gag, Pol, and Nef proteins including multiple CD4 and CD8 T cell epitopes functionally associated with HIV control. Heterologous DNA-TMEP/MVA-B regimen induced higher HIV-1-specific CD8 T cell responses with broader epitope recognition and higher polyfunctional profile than the homologous DNA-TMEP/DNA-TMEP or the heterologous DNA-GPN/MVA-B combinations. Moreover, higher HIV-1-specific CD4 and Tfh immune responses were also detected using this regimen. After MVA-B boost, the magnitude of the anti-VACV CD8 T cell response was significantly compromised in DNA-TMEP-primed animals. Our results revealed the immunological potential of DNA-TMEP prime/MVA-B boost regimen and supported the application of these combined vectors in HIV-1 prevention and/or therapy.

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130 Immunogenic potential of chimeric antigen receptor (CAR)-engineered T cells expressing inducible nuclease-deactivated SpCas9 (dCas9)

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0130 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A143-A143

Author(s):

Dharmeshkumar Patel ◽

Angshumala Goswami ◽

Vitaly Balan ◽

Zhifen Yang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Peptide Sequence ◽

T Cell Epitopes ◽

Cell Responses ◽

Car T Cells ◽

Car T

BackgroundThe application of CRISPR-Cas9 for personalized medicine is potentially revolutionary for the treatment of several diseases including cancer. However, the bacterial origin of the Cas9 protein raises concerns about immunogenicity. Recent ELISA-based assays detected antibodies against Cas9 from Streptococcus pyogenes (SpCas9) and Staphylococcus aureus (SaCas9) in 5–10% of sera from 343 normal healthy individuals.1,2 SpCas9-specific memory CD8 T cell responses were not demonstrated in those individuals. To date, there are no conclusive studies assessing whether CRISPR-Cas9-modified CAR-T could raise CD8 T cell-mediated immunogenicity in humans. Refuge CAR-T cell platform employs an inducible, non-gene editing, nuclease deactivated Cas9 (dCas9) to modulate gene expression in response to external stimuli such as antigen-dependent CAR signaling to suppress PD-1 expression.MethodsIn the present study, we analyzed two putative HLA-A*02:01 and two HLA-B*07:02-associated SpCas9 T cell epitopes. The candidate epitopes were derived from a prediction algorithm that incorporates T cell receptor contact residue hydrophobicity and HLA binding affinity. We engaged in-vitro sensitization (IVS) assay to identify immunogenic potential of dCas9 peptides.ResultsAutologous IVS assay of T cells in two healthy donor PBMCs identified CD8-T cell responses after two rounds of stimulation against only one HLA-A*02:01-associated Cas9 peptide (sequence NLIALSLGL) P1– while the other candidate epitopes did not elicit any response. Dextramer analysis demonstrated that 15% of CD8+ T cells were specific for P1 and ~11% of CD8+ cells produced INFG upon challenge with P1-loaded T2 cells.ConclusionsOur in-vitro sensitization assay was able to demonstrate that dCas9 epitope P1 is immunogenic and may elicit adaptive immune response against gene edited CAR-T cells. Endogenous processing and presentation of P1 and other putative epitopes by Refuge CAR-T cells are currently being analyzed.AcknowledgementsRefuge Biotechnologies Inc. Menlo Park, California, 94025Trial RegistrationN/AEthics ApprovalN/AConsentN/AReferencesSimhadri VL, McGill J, McMahon S, Wang J, Jiang H, Sauna ZE. Prevalence of Pre-existing Antibodies to CRISPR-Associated Nuclease Cas9 in the USA Population. Mol Ther Methods Clin Dev 2018;10:105–112. Published 2018 Jun 15. doi:10.1016/j.omtm.2018.06.006Ferdosi SR, Ewaisha R, Moghadam F, et al. Multifunctional CRISPR-Cas9 with engineered immunosilenced human T cell epitopes. Nat Commun2019;10(1):1842. Published 2019 Apr 23. doi:10.1038/s41467-019-09693-x

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Minimal cross-over between mutations associated with Omicron variant of SARS-CoV-2 and CD8+ T cell epitopes identified in COVID-19 convalescent individuals

10.1101/2021.12.06.471446 ◽

2021 ◽

Author(s):

Andrew Redd ◽

Alessandra Nardin ◽

Hassen Kared ◽

Evan M Bloch ◽

Brian Abel ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

The United States ◽

Single Amino Acid ◽

T Cell Epitopes ◽

Peripheral Blood Mononuclear ◽

Cell Responses ◽

Single Amino Acid Change ◽

Hla Haplotypes

There is a growing concern that ongoing evolution of SARS-CoV-2 could lead to variants of concern (VOC) that are capable of avoiding some or all of the multi-faceted immune response generated by both prior infection or vaccination, with the recently described B.1.1.529 (Omicron) VOC being of particular interest. Peripheral blood mononuclear cell samples from PCR-confirmed, recovered COVID-19 convalescent patients (n=30) infected with SARS-CoV-2 in the United States collected in April and May 2020 who possessed at least one or more of six different HLA haplotypes were selected for examination of their anti-SARS-CoV-2 CD8+ T-cell responses using a multiplexed peptide-MHC tetramer staining approach. This analysis examined if the previously identified viral epitopes targeted by CD8+ T-cells in these individuals (n=52 distinct epitopes) are mutated in the newly described Omicron VOC (n=50 mutations). Within this population, only one low-prevalence epitope from the Spike protein restricted to two HLA alleles and found in 2/30 (7%) individuals contained a single amino acid change associated with the Omicron VOC. These data suggest that virtually all individuals with existing anti-SARS-CoV-2 CD8+ T-cell responses should recognize the Omicron VOC, and that SARS-CoV-2 has not evolved extensive T-cell escape mutations at this time.

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Cellular immune selection with hepatitis C virus persistence in humans

Journal of Experimental Medicine ◽

10.1084/jem.20050121 ◽

2005 ◽

Vol 201 (11) ◽

pp. 1741-1752 ◽

Cited By ~ 210

Author(s):

Andrea L. Cox ◽

Timothy Mosbruger ◽

Qing Mao ◽

Zhi Liu ◽

Xiao-Hong Wang ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Viral Escape ◽

Sequence Evolution ◽

T Cell Epitopes ◽

Cell Responses ◽

Cellular Immune

Hepatitis C virus (HCV) infection frequently persists despite substantial virus-specific cellular immune responses. To determine if immunologically driven sequence variation occurs with HCV persistence, we coordinately analyzed sequence evolution and CD8+ T cell responses to epitopes covering the entire HCV polyprotein in subjects who were followed prospectively from before infection to beyond the first year. There were no substitutions in T cell epitopes for a year after infection in a subject who cleared viremia. In contrast, in subjects with persistent viremia and detectable T cell responses, we observed substitutions in 69% of T cell epitopes, and every subject had a substitution in at least one epitope. In addition, amino acid substitutions occurred 13-fold more often within than outside T cell epitopes (P < 0.001, range 5–38). T lymphocyte recognition of 8 of 10 mutant peptides was markedly reduced compared with the initial sequence, indicating viral escape. Of 16 nonenvelope substitutions that occurred outside of known T cell epitopes, 8 represented conversion to consensus (P = 0.015). These findings reveal two distinct mechanisms of sequence evolution involved in HCV persistence: viral escape from CD8+ T cell responses and optimization of replicative capacity.

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