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Title: Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E

Abstract

Major histocompatibility complex (MHC)-E is a highly conserved, ubiquitously expressed, nonclassical, MHC-Ib molecule with limited polymorphism primarily involved in regulation of NK cell reactivity via interaction with NKG2/CD94 receptors. We found that vaccination of rhesus macaques with Rh157.5/.4 gene-deleted rhesus Cytomegalovirus (RhCMV) vectors uniquely diverts MHC-E function to presentation of highly diverse peptide epitopes to CD8α/β + T cells, approximately 4 distinct epitopes per 100 amino acids, in all tested protein antigens. Computational structural analysis revealed that a relatively stable, open binding groove in MHC-E attains broad peptide binding specificity by imposing a similar backbone configuration on bound peptides with few restrictions based on amino acid side chains. Since MHC-E is up-regulated on cells infected with HIV/SIV and other persistent viruses to evade NK cell activity, MHC-E-restricted CD8 + T cell responses have the potential to exploit pathogen immune evasion adaptations, a capability that might endow these unconventional responses with superior efficacy.

Authors:
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Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH); Work for Others (WFO)
OSTI Identifier:
1355834
Alternate Identifier(s):
OSTI ID: 1304811
Report Number(s):
LA-UR-15-24868
Journal ID: ISSN 0036-8075; science.aac9475
Grant/Contract Number:  
AC52-06NA25396; 1K01DK094941; 5U01DK89572; DK104211; 5-CDA2014210-A-N; 1R01DK081166
Resource Type:
Published Article
Journal Name:
Science
Additional Journal Information:
Journal Name: Science Journal Volume: 351 Journal Issue: 6274; Journal ID: ISSN 0036-8075
Publisher:
American Association for the Advancement of Science (AAAS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science; CD8+ T; Major histocompatibility complex E; MHC-E; HIV

Citation Formats

Hansen, S. G., Wu, H. L., Burwitz, B. J., Hughes, C. M., Hammond, K. B., Ventura, A. B., Reed, J. S., Gilbride, R. M., Ainslie, E., Morrow, D. W., Ford, J. C., Selseth, A. N., Pathak, R., Malouli, D., Legasse, A. W., Axthelm, M. K., Nelson, J. A., Gillespie, G. M., Walters, L. C., Brackenridge, S., Sharpe, H. R., Lopez, C. A., Fruh, K., Korber, B. T., McMichael, A. J., Gnanakaran, S., Sacha, J. B., and Picker, L. J. Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E. United States: N. p., 2016. Web. doi:10.1126/science.aac9475.
Hansen, S. G., Wu, H. L., Burwitz, B. J., Hughes, C. M., Hammond, K. B., Ventura, A. B., Reed, J. S., Gilbride, R. M., Ainslie, E., Morrow, D. W., Ford, J. C., Selseth, A. N., Pathak, R., Malouli, D., Legasse, A. W., Axthelm, M. K., Nelson, J. A., Gillespie, G. M., Walters, L. C., Brackenridge, S., Sharpe, H. R., Lopez, C. A., Fruh, K., Korber, B. T., McMichael, A. J., Gnanakaran, S., Sacha, J. B., & Picker, L. J. Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E. United States. doi:10.1126/science.aac9475.
Hansen, S. G., Wu, H. L., Burwitz, B. J., Hughes, C. M., Hammond, K. B., Ventura, A. B., Reed, J. S., Gilbride, R. M., Ainslie, E., Morrow, D. W., Ford, J. C., Selseth, A. N., Pathak, R., Malouli, D., Legasse, A. W., Axthelm, M. K., Nelson, J. A., Gillespie, G. M., Walters, L. C., Brackenridge, S., Sharpe, H. R., Lopez, C. A., Fruh, K., Korber, B. T., McMichael, A. J., Gnanakaran, S., Sacha, J. B., and Picker, L. J. Thu . "Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E". United States. doi:10.1126/science.aac9475.
@article{osti_1355834,
title = {Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E},
author = {Hansen, S. G. and Wu, H. L. and Burwitz, B. J. and Hughes, C. M. and Hammond, K. B. and Ventura, A. B. and Reed, J. S. and Gilbride, R. M. and Ainslie, E. and Morrow, D. W. and Ford, J. C. and Selseth, A. N. and Pathak, R. and Malouli, D. and Legasse, A. W. and Axthelm, M. K. and Nelson, J. A. and Gillespie, G. M. and Walters, L. C. and Brackenridge, S. and Sharpe, H. R. and Lopez, C. A. and Fruh, K. and Korber, B. T. and McMichael, A. J. and Gnanakaran, S. and Sacha, J. B. and Picker, L. J.},
abstractNote = {Major histocompatibility complex (MHC)-E is a highly conserved, ubiquitously expressed, nonclassical, MHC-Ib molecule with limited polymorphism primarily involved in regulation of NK cell reactivity via interaction with NKG2/CD94 receptors. We found that vaccination of rhesus macaques with Rh157.5/.4 gene-deleted rhesus Cytomegalovirus (RhCMV) vectors uniquely diverts MHC-E function to presentation of highly diverse peptide epitopes to CD8α/β+ T cells, approximately 4 distinct epitopes per 100 amino acids, in all tested protein antigens. Computational structural analysis revealed that a relatively stable, open binding groove in MHC-E attains broad peptide binding specificity by imposing a similar backbone configuration on bound peptides with few restrictions based on amino acid side chains. Since MHC-E is up-regulated on cells infected with HIV/SIV and other persistent viruses to evade NK cell activity, MHC-E-restricted CD8+ T cell responses have the potential to exploit pathogen immune evasion adaptations, a capability that might endow these unconventional responses with superior efficacy.},
doi = {10.1126/science.aac9475},
journal = {Science},
number = 6274,
volume = 351,
place = {United States},
year = {2016},
month = {1}
}

Journal Article:
Free Publicly Available Full Text
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DOI: 10.1126/science.aac9475

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Cited by: 56 works
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