scholarly journals Transmembrane helices are an overlooked and evolutionarily conserved source of major histocompatibility complex class II epitopes

2021 ◽  
Author(s):  
Richel Bilderbeek ◽  
Maksim Baranov ◽  
Frans Bianchi ◽  
Geert van den Bogaart
Keyword(s):  
T Cell ◽  
Membrane Proteins ◽  
T Cell Responses ◽  
Nucleotide Polymorphisms ◽  
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 haplotypes of histocompatibility complex class I (MHC-I) are relatively hydrophobic, therefor 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 over-presentation of TMH-derived peptides is general, as it is predicted for bacteria and viruses and for both MHC-I and MHC-II. 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 respond more to membrane proteins, because these are evolutionary more conserved. We speculate that TMHs therefor are less prone to escape mutations that enable pathogens to evade T cell responses.

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.

scholarly journals The Frequency of Vaccine-Induced T-Cell Responses Does Not Predict the Rate of Acquisition after Repeated Intrarectal SIVmac239 Challenges inMamu-B*08+Rhesus Macaques

2018 ◽  
Vol 93 (5) ◽  
Author(s):  
Mauricio A. Martins ◽  
Lucas Gonzalez-Nieto ◽  
Young C. Shin ◽  
Aline Domingues ◽  
Martin J. Gutman ◽  
...  
Keyword(s):  
T Cell ◽  
Rhesus Macaques ◽  
T Cell Responses ◽  
Complex Class ◽  
Class I Mhc ◽  
Mhc I ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACTApproximately 50% of rhesus macaques (RMs) expressing the major histocompatibility complex class I (MHC-I) alleleMamu-B*08spontaneously control chronic-phase viremia after infection with the pathogenic simian immunodeficiency virus mac239 (SIVmac239) clone. CD8+T-cell responses in these animals are focused on immunodominant Mamu-B*08-restricted SIV epitopes in Vif and Nef, and prophylactic vaccination with these epitopes increases the incidence of elite control in SIVmac239-infectedMamu-B*08-positive (Mamu-B*08+) RMs. Here we evaluated if robust vaccine-elicited CD8+T-cell responses against Vif and Nef can prevent systemic infection inMamu-B*08+RMs following mucosal SIV challenges. TenMamu-B*08+RMs were vaccinated with a heterologous prime/boost/boost regimen encoding Vif and Nef, while six sham-vaccinated MHC-I-matched RMs served as the controls for this experiment. Vaccine-induced CD8+T cells against Mamu-B*08-restricted SIV epitopes reached high frequencies in blood but were present at lower levels in lymph node and gut biopsy specimens. Following repeated intrarectal challenges with SIVmac239, all control RMs became infected by the sixth SIV exposure. By comparison, four vaccinees were still uninfected after six challenges, and three of them remained aviremic after 3 or 4 additional challenges. The rate of SIV acquisition in the vaccinees was numerically lower (albeit not statistically significantly) than that in the controls. However, peak viremia was significantly reduced in infected vaccinees compared to control animals. We found no T-cell markers that distinguished vaccinees that acquired SIV infection from those that did not. Additional studies will be needed to validate these findings and determine if cellular immunity can be harnessed to prevent the establishment of productive immunodeficiency virus infection.IMPORTANCEIt is generally accepted that the antiviral effects of vaccine-induced classical CD8+T-cell responses against human immunodeficiency virus (HIV) are limited to partial reductions in viremia after the establishment of productive infection. Here we show that rhesus macaques (RMs) vaccinated with Vif and Nef acquired simian immunodeficiency virus (SIV) infection at a lower (albeit not statistically significant) rate than control RMs following repeated intrarectal challenges with a pathogenic SIV clone. All animals in the present experiment expressed the elite control-associated major histocompatibility complex class I (MHC-I) molecule Mamu-B*08 that binds immunodominant epitopes in Vif and Nef. Though preliminary, these results provide tantalizing evidence that the protective efficacy of vaccine-elicited CD8+T cells may be greater than previously thought. Future studies should examine if vaccine-induced cellular immunity can prevent systemic viral replication in RMs that do not express MHC-I alleles associated with elite control of SIV infection.

scholarly journals Differential Antigen Presentation Kinetics of CD8+ T-Cell Epitopes Derived from the Same Viral Protein

2008 ◽  
Vol 82 (18) ◽  
pp. 9293-9298 ◽  
Author(s):  
Jonah B. Sacha ◽  
Matthew R. Reynolds ◽  
Matthew B. Buechler ◽  
Chungwon Chung ◽  
Anna K. Jonas ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Protein ◽  
Cd8 T Cell ◽  
T Cell Epitopes ◽  
Complex Class ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Peptide Presentation ◽  
Kinetics Of

ABSTRACT The kinetics of peptide presentation by major histocompatibility complex class I (MHC-I) molecules may contribute to the efficacy of CD8+ T cells. Whether all CD8+ T-cell epitopes from a protein are presented by the same MHC-I molecule with similar kinetics is unknown. Here we show that CD8+ T-cell epitopes derived from SIVmac239 Gag are presented with markedly different kinetics. We demonstrate that this discrepancy in presentation is not related to immunodominance but instead is due to differential requirements for epitope generation. These results illustrate that significant differences in presentation kinetics can exist among CD8+ T-cell epitopes derived from the same viral protein.

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.

Molecular challenges imposed by MHC-I restricted long epitopes on T cell immunity

2017 ◽  
Vol 398 (9) ◽  
pp. 1027-1036 ◽  
Author(s):  
Tracy M. Josephs ◽  
Emma J. Grant ◽  
Stephanie Gras
Keyword(s):  
Major Histocompatibility Complex ◽  
Immune System ◽  
T Cell ◽  
T Cell Immunity ◽  
Complex Class ◽  
Small Peptides ◽  
Mhc I ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Cell Immunity

Abstract It has widely been accepted that major histocompatibility complex class I molecules (MHC-I) are limited to binding small peptides of 8–10 residues in length. However, this consensus has recently been challenged with the identification of longer peptides (≥11 residues) that can also elicit cytotoxic CD8+ T cell responses. Indeed, a growing number of studies demonstrate that these non-canonical epitopes are important targets for the immune system. As long epitopes represent up to 10% of the peptide repertoire bound to MHC-I molecules, here we review their impact on antigen presentation by MHC-I, TCR recognition, and T cell immunity.

scholarly journals Processing and Major Histocompatibility Complex Class II Presentation of Legionella pneumophila Antigens by Infected Macrophages

2005 ◽  
Vol 73 (4) ◽  
pp. 2336-2343 ◽  
Author(s):  
Annie Neild ◽  
Takahiro Murata ◽  
Craig R. Roy
Keyword(s):  
T Cells ◽  
T Cell ◽  
Legionella Pneumophila ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Complex Class ◽  
Wild Type ◽  
Mhc Ii ◽  
Cell Responses ◽  
Histocompatibility Complex

ABSTRACT To better understand interactions between the intracellular pathogen Legionella pneumophila and macrophages (Mφs), host and bacterial determinants important for presentation of antigens on major histocompatibility complex class II molecules (MHC-II) were investigated. It was determined that immune CD4 T-cell responses to murine bone marrow-derived Mφs (BMφs) infected with wild-type L. pneumophila were higher than the responses to avirulent dotA mutant bacteria. Although this enhanced response by immune T cells required modulation of vacuole transport mediated by the Dot/Icm system, it did not require intracellular replication of L. pneumophila. Intracellular cytokine staining identified a population of immune CD4 T cells that produced gamma interferon upon incubation with BMφs infected with wild-type L. pneumophila that did not respond to Mφ infection with dotA mutant bacteria. Endocytic processing was required for presentation of L. pneumophila antigens on MHC-II as determined by a defect in CD4 T-cell responses when the pH of BMφ endosomes was neutralized with chloroquine. Investigation of MHC-II presentation of antigens by BMφs infected with L. pneumophila icmR, icmW, and icmS mutants indicated that these mutants have an intermediate presentation phenotype relative to those of wild-type and dotA mutant bacteria. In addition, it was found that antigens from dot and icm mutants are presented earlier than antigens from wild-type L. pneumophila. Although immune CD4 T-cell responses to proteins secreted by the L. pneumophila Lsp system were not detected, it was found that the Lsp system is important for priming L. pneumophila-specific T cells in vivo. These data indicate that optimal antigen processing and MHC-II presentation to immune CD4 T cells involves synthesis of L. pneumophila proteins in an endoplasmic reticulum-derived compartment followed by transport to lysosomes.

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