scholarly journals Analysis of Pigtail Macaque Major Histocompatibility Complex Class I Molecules Presenting Immunodominant Simian Immunodeficiency Virus Epitopes

2005 ◽  
Vol 79 (2) ◽  
pp. 684-695 ◽  
Author(s):  
Miranda Z. Smith ◽  
C. Jane Dale ◽  
Robert De Rose ◽  
Ivan Stratov ◽  
Caroline S. Fernandez ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class I ◽  
T Cell Responses ◽  
Class I ◽  
Pigtail Macaque ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Pigtail Macaques

ABSTRACT Successful human immunodeficiency virus (HIV) vaccines will need to induce effective T-cell immunity. We studied immunodominant simian immunodeficiency virus (SIV) Gag-specific T-cell responses and their restricting major histocompatibility complex (MHC) class I alleles in pigtail macaques (Macaca nemestrina), an increasingly common primate model for the study of HIV infection of humans. CD8+ T-cell responses to an SIV epitope, Gag164 - 172KP9, were present in at least 15 of 36 outbred pigtail macaques. The immunodominant KP9-specific response accounted for the majority (mean, 63%) of the SIV Gag response. Sequencing from six macaques identified 7 new Mane-A and 13 new Mane-B MHC class I alleles. One new allele, Mane-A*10, was common to four macaques that responded to the KP9 epitope. We adapted reference strand-mediated conformational analysis (RSCA) to MHC class I genotype M. nemestrina. Mane-A*10 was detected in macaques presenting KP9 studied by RSCA but was absent from non-KP9-presenting macaques. Expressed on class I-deficient cells, Mane-A*10, but not other pigtail macaque MHC class I molecules, efficiently presented KP9 to responder T cells, confirming that Mane-A*10 restricts the KP9 epitope. Importantly, naïve pigtail macaques infected with SIVmac251 that respond to KP9 had significantly reduced plasma SIV viral levels (log10 0.87 copies/ml; P = 0.025) compared to those of macaques not responding to KP9. The identification of this common M. nemestrina MHC class I allele restricting a functionally important immunodominant SIV Gag epitope establishes a basis for studying CD8+ T-cell responses against AIDS in an important, widely available nonhuman primate species.

scholarly journals Putative Immunodominant Human Immunodeficiency Virus-Specific CD8+ T-Cell Responses Cannot Be Predicted by Major Histocompatibility Complex Class I Haplotype

2000 ◽  
Vol 74 (19) ◽  
pp. 9144-9151 ◽  
Author(s):  
Michael R. Betts ◽  
Joseph P. Casazza ◽  
Brent A. Patterson ◽  
Shar Waldrop ◽  
Wendy Trigona ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
T Cell Responses ◽  
T Cell Response ◽  
Class I ◽  
Complex Class ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus

ABSTRACT Recent studies of human immunodeficiency virus (HIV)-specific CD8+ T cells have focused on responses to single, usually HLA-A2-restricted epitopes as surrogate measures of the overall response to HIV. However, the assumption that a response to one epitope is representative of the total response is unconfirmed. Here we assess epitope immunodominance and HIV-specific CD8+ T-cell response complexity using cytokine flow cytometry to examine CD8+ T-cell responses in 11 HLA-A2+HIV+ individuals. Initial studies demonstrated that only 4 of 11 patients recognized the putative immunodominant HLA-A2-restricted p17 epitope SLYNTVATL, suggesting that the remaining subjects might lack significant HIV-specific CD8+ T-cell responses. However, five of six SLYNTVATL nonresponders recognized other HIV epitopes, and two of four SLYNTVATL responders had greater responses to HIV peptides restricted by other class I alleles. In several individuals, no HLA-A2-restricted epitopes were recognized, but CD8+ T-cell responses were detected to epitopes restricted by other HLA class I alleles. These data indicate that an individual's overall CD8+ T-cell response to HIV is not adequately represented by the response to a single epitope and that individual major histocompatibility complex class I alleles do not predict an immunodominant response restricted by that allele. Accurate quantification of total HIV-specific CD8+ T-cell responses will require assessment of the response to all possible epitopes.

scholarly journals Novel Role of CD8+ T Cells and Major Histocompatibility Complex Class I Genes in the Generation of Protective CD4+ Th1 Responses during Retrovirus Infection in Mice

2002 ◽  
Vol 76 (16) ◽  
pp. 7942-7948 ◽  
Author(s):  
Karin E. Peterson ◽  
Ingunn Stromnes ◽  
Ron Messer ◽  
Kim Hasenkrug ◽  
Bruce Chesebro
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
T Cell Responses ◽  
Class I ◽  
Major Histocompatibility ◽  
Cell Responses ◽  
Histocompatibility Complex

ABSTRACT CD4+ Th1 responses to virus infections are often necessary for the development and maintenance of virus-specific CD8+ T-cell responses. However, in the present study with Friend murine retrovirus (FV), the reverse was also found to be true. In the absence of a responder H-2b allele at major histocompatibility complex (MHC) class II loci, a single H-2Db MHC class I allele was sufficient for the development of a CD4+ Th1 response to FV. This effect of H-2Db on CD4+ T-cell responses was dependent on CD8+ T cells, as demonstrated by depletion studies. A direct effect of CD8+ T-cell help in the development of CD4+ Th1 responses to FV was also shown in vaccine studies. Vaccination of nonresponder H-2a/a mice induced FV-specific responses of H-2Dd -restricted CD8+ cytotoxic T lymphocytes (CTL). Adoptive transfer of vaccine-primed CD8+ T cells to naive H-2a/a mice prior to infection resulted in the generation of FV-specific CD4+ Th1 responses. This novel helper effect of CD8+ T cells could be an important mechanism in the development of CD4+ Th1 responses following vaccinations that induce CD8+ CTL responses. The ability of MHC class I genes to facilitate CD4+ Th1 development could also be considerable evolutionary advantage by allowing a wider variety of MHC genotypes to generate protective immune responses against intracellular pathogens.

scholarly journals Infection with “Escaped” Virus Variants Impairs Control of Simian Immunodeficiency Virus SIVmac239 Replication in Mamu-B*08-Positive Macaques

2009 ◽  
Vol 83 (22) ◽  
pp. 11514-11527 ◽  
Author(s):  
Laura E. Valentine ◽  
John T. Loffredo ◽  
Alex T. Bean ◽  
Enrique J. León ◽  
Caitlin E. MacNair ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Mhc Class I ◽  
T Cell Responses ◽  
Class I ◽  
Wild Type ◽  
Viral Loads ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT An understanding of the mechanism(s) by which some individuals spontaneously control human immunodeficiency virus (HIV)/simian immunodeficiency virus replication may aid vaccine design. Approximately 50% of Indian rhesus macaques that express the major histocompatibility complex (MHC) class I allele Mamu-B*08 become elite controllers after infection with simian immunodeficiency virus SIVmac239. Mamu-B*08 has a binding motif that is very similar to that of HLA-B27, a human MHC class I allele associated with the elite control of HIV, suggesting that SIVmac239-infected Mamu-B*08-positive (Mamu-B*08+ ) animals may be a good model for the elite control of HIV. The association with MHC class I alleles implicates CD8+ T cells and/or natural killer cells in the control of viral replication. We therefore introduced point mutations into eight Mamu-B*08-restricted CD8+ T-cell epitopes to investigate the contribution of epitope-specific CD8+ T-cell responses to the development of the control of viral replication. Ten Mamu-B*08 + macaques were infected with this mutant virus, 8X-SIVmac239. We compared immune responses and viral loads of these animals to those of wild-type SIVmac239-infected Mamu-B*08 + macaques. The five most immunodominant Mamu-B*08-restricted CD8+ T-cell responses were barely detectable in 8X-SIVmac239-infected animals. By 48 weeks postinfection, 2 of 10 8X-SIVmac239-infected Mamu-B*08+ animals controlled viral replication to <20,000 viral RNA (vRNA) copy equivalents (eq)/ml plasma, while 10 of 15 wild-type-infected Mamu-B*08+ animals had viral loads of <20,000 vRNA copy eq/ml (P = 0.04). Our results suggest that these epitope-specific CD8+ T-cell responses may play a role in establishing the control of viral replication in Mamu-B*08 + macaques.

scholarly journals Mauritian Cynomolgus Macaques Share Two Exceptionally Common Major Histocompatibility Complex Class I Alleles That Restrict Simian Immunodeficiency Virus-Specific CD8+ T Cells

2009 ◽  
Vol 83 (12) ◽  
pp. 6011-6019 ◽  
Author(s):  
Benjamin J. Burwitz ◽  
Chad J. Pendley ◽  
Justin M. Greene ◽  
Ann M. Detmer ◽  
Jennifer J. Lhost ◽  
...  
Keyword(s):  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Mhc Class I ◽  
Nonhuman Primate ◽  
T Cell Responses ◽  
Class I ◽  
Major Histocompatibility ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Cynomolgus Macaques

ABSTRACT Vaccines that elicit CD8+ T-cell responses are routinely tested for immunogenicity in nonhuman primates before advancement to clinical trials. Unfortunately, the magnitude and specificity of vaccine-elicited T-cell responses are variable in currently utilized nonhuman primate populations, owing to heterogeneity in major histocompatibility (MHC) class I genetics. We recently showed that Mauritian cynomolgus macaques (MCM) have unusually simple MHC genetics, with three common haplotypes encoding a shared pair of MHC class IA alleles, Mafa-A*25 and Mafa-A*29. Based on haplotype frequency, we hypothesized that CD8+ T-cell responses restricted by these MHC class I alleles would be detected in nearly all MCM. We examine here the frequency and functionality of these two alleles, showing that 88% of MCM express Mafa-A*25 and Mafa-A*29 and that animals carrying these alleles mount three newly defined simian immunodeficiency virus-specific CD8+ T-cell responses. The epitopes recognized by each of these responses accumulated substitutions consistent with immunologic escape, suggesting these responses exert antiviral selective pressure. The demonstration that Mafa-A*25 and Mafa-A*29 restrict CD8+ T-cell responses that are shared among nearly all MCM indicates that these animals are an advantageous nonhuman primate model for comparing the immunogenicity of vaccines that elicit CD8+ T-cell responses.

scholarly journals High-throughput identification of MHC class I binding peptides using an ultradense peptide array

2019 ◽  
Author(s):  
Amelia K. Haj ◽  
Meghan E. Breitbach ◽  
David A. Baker ◽  
Mariel S. Mohns ◽  
Gage K. Moreno ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class I ◽  
High Throughput ◽  
Vaccine Development ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Class I ◽  
Peptide Array ◽  
Cell Responses ◽  
Immunodeficiency Virus

AbstractRational vaccine development and evaluation requires identifying and measuring the magnitude of epitope-specific CD8 T cell responses. However, conventional CD8 T cell epitope discovery methods are labor-intensive and do not scale well. Here, we accelerate this process by using an ultradense peptide array as a high-throughput tool for screening peptides to identify putative novel epitopes. In a single experiment, we directly assess the binding of four common Indian rhesus macaque MHC class I molecules – Mamu-A1*001, -A1*002, -B*008, and -B*017 – to approximately 61,000 8-mer, 9-mer, and 10-mer peptides derived from the full proteomes of 82 simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) isolates. Many epitope-specific CD8 T cell responses restricted by these four MHC molecules have already been identified in SIVmac239, providing an ideal dataset for validating the array; up to 64% of these known epitopes are found in the top 192 SIVmac239 peptides with the most intense MHC binding signals in our experiment. To assess whether the peptide array identified putative novel CD8 T cell epitopes, we validated the method by IFN-γ ELISPOT assay and found three novel peptides that induced CD8 T cell responses in at least two Mamu-A1*001-positive animals; two of these were validated by ex vivo tetramer staining. This high-throughput identification of peptides that bind class I MHC will enable more efficient CD8 T cell response profiling for vaccine development, particularly for pathogens with complex proteomes where few epitope-specific responses have been defined.

608 Immunodominant listeria epitopes compete with vaccine-directed cd8+ t-cell responses rescued by peptide-MHC stabilizing modifications

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A644-A644
Author(s):  
John Flickinger ◽  
Jagmohan Singh ◽  
Yanki Yarman ◽  
Robert Carlson ◽  
Scott Waldman ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
T Cell ◽  
Cell Line ◽  
Mhc Class I ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Class I ◽  
Peptide Ligand ◽  
Altered Peptide Ligand ◽  
Cell Responses

BackgroundThe Gram-positive bacterium Listeria monocytogenes (Lm) is a promising vector for cancer immunotherapy due to its ability to directly infect antigen-presenting cells, induce potent CD8+ T-cell immunity, and remodel immunosuppressive tumor microenvironments.1 Recent clinical trials have demonstrated safety and immunogenicity of Lm-based cancer vaccines in lung, cervical, pancreatic, and other cancers. In colorectal cancer, the transmembrane receptor guanylyl cyclase C (GUCY2C) is an emerging target for immunotherapy.2 Here, we examined the immunogenicity of a recombinant strain of Listeria monocytogenes secreting GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination induced robust Lm-specific CD8+ T-cell immunity but failed to prime GUCY2C-specific CD8+ T-cell responses. These studies explore the hypothesis that immunodominant Lm antigens suppress primary immunity to subdominant GUCY2C epitopes in Lm-GUCY2CMethodsLm-GUCY2C expresses the extracellular domain of mouse GUCY2C23-429 downstream of an ActA promoter integrated into the genome of the live, attenuated delta actA delta inlB Lm strain. Altered peptide ligands were designed based on NetMHCpan 4.0 peptide-MHC binding algorithms and similarly cloned into Lm. Peptide-MHC class I complex stability was quantified by FACS-based surface peptide-MHC dissociation on the TAP-deficient cell line, RMA-S H-2Kd.3In vivo efficacy studies employed IFNγ-ELISpot quantification of T-cell responses and tumor challenge studies with the CT26 colorectal cancer cell line. Adenovirus expressing GUCY2C was used as a positive control.2 4ResultsLm-GUCY2C vaccination of BALB/c mice generated Lm-specific CD8+ T-cell responses but an absence of GUCY2C-specific immunity. Peptide-MHC stability studies revealed poor stability of the dominant GUCY2C254-262 epitope complexed with H-2Kd compared to H-2Kd-restricted Lm epitopes derived from the LLO and p60 Lm antigens. Mutation of the GUCY2C254-262 peptide at critical anchoring residues for binding H-2Kd revealed that the altered peptide ligand with an F255Y mutation significantly improved the stability of the GUCY2C254-262-H-2Kd complex. Similarly, vaccination of mice with recombinant Lm-GUCY2C expressing the altered peptide ligand (Lm-GUCY2CF255Y) restored GUCY2C immunogenicity and antitumor immunity.ConclusionsImmunodominant Lm antigens may interfere with immune responses directed to the vaccine target antigen GUCY2C by competing with GUCY2C epitope for MHC class I binding and presentation. Moreover, use of a substituted GUCY2C -peptide ligand with enhanced peptide-MHC class I stability restored GUCY2C-specific immunity in the context of Lm-GUCY2C, an approach that can be translated to patients. Importantly, these studies also suggest that ongoing Lm-based vaccine development programs targeting a variety of antigens in other cancer types may be similarly limited by the immunodominance of Lm epitopes.AcknowledgementsThe authors thank Dr. Peter Lauer for providing the pPL2 integration vector used in cloning Lm-GUCY2C and Dr. Sean Murphy for providing the RMA-S H-2Kd cell line.Ethics ApprovalStudies were approved by the Thomas Jefferson University IACUC (Protocol # 01956).ReferencesFlickinger JC, Rodeck U, Snook AE. Listeria monocytogenes as a Vector for Cancer Immunotherapy: Current Understanding and Progress. Vaccines (Basel) 2018;6. doi:10.3390/vaccines6030048.Snook AE, Baybutt TR, Xiang B, Abraham TS, Flickinger JC, Hyslop T, et al. Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients. J Immunother Cancer 2019;7:104. doi:10.1186/s40425-019-0576-2.Müllbacher A, Lobigs M, Kos FJ, Langman R. Alloreactive cytotoxic T-cell function, peptide nonspecific. Scand J Immunol 1999;49:563–9.Flickinger J. JC, Singh J, Carlson R, Leong E, Baybutt T, Barton J, et al. Chimeric Ad5.F35 vector evades anti-adenovirus serotype 5 neutralization opposing GUCY2C-targeted antitumor immunity. J Immunother Cancer 2020.

Natural CD8 + T-cell responses against MHC class I epitopes of the HER-2/ neu oncoprotein in patients with epithelial tumors

2003 ◽  
Vol 52 (12) ◽  
pp. 771-779 ◽  
Author(s):  
Panagiota A. Sotiropoulou ◽  
Sonia A. Perez ◽  
Volfgang Voelter ◽  
Hartmut Echner ◽  
Ioannis Missitzis ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class I ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Class I ◽  
Cell Responses ◽  
Epithelial Tumors ◽  
Her 2

scholarly journals Transmembrane Helices Are an Over-Presented and Evolutionarily Conserved Source of Major Histocompatibility Complex Class I and II Epitopes

2022 ◽  
Vol 12 ◽  
Author(s):  
Richèl J. C. Bilderbeek ◽  
Maksim V. Baranov ◽  
Geert van den Bogaart ◽  
Frans Bianchi
Keyword(s):  
T Cell ◽  
Membrane Proteins ◽  
T Cell Responses ◽  
Class I ◽  
Complex Class ◽  
Transmembrane Helices ◽  
Class I Mhc ◽  
Mhc I ◽  
Cell Responses ◽  
Histocompatibility Complex

Cytolytic T cell responses are predicted to be biased towards membrane proteins. The peptide-binding grooves of most alleles of histocompatibility complex class I (MHC-I) are relatively hydrophobic, therefore peptide fragments derived from human transmembrane helices (TMHs) are predicted to be presented more often as would be expected based on their abundance in the proteome. However, the physiological reason of why membrane proteins might be over-presented is unclear. In this study, we show that the predicted over-presentation of TMH-derived peptides is general, as it is predicted for bacteria and viruses and for both MHC-I and MHC-II, and confirmed by re-analysis of epitope databases. Moreover, we show that TMHs are evolutionarily more conserved, because single nucleotide polymorphisms (SNPs) are present relatively less frequently in TMH-coding chromosomal regions compared to regions coding for extracellular and cytoplasmic protein regions. Thus, our findings suggest that both cytolytic and helper T cells are more tuned to respond to membrane proteins, because these are evolutionary more conserved. We speculate that TMHs are less prone to mutations that enable pathogens to evade T cell responses.

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