@article{b516e9790a404000b4ad8c53f31dddbc,
title = "Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E",
abstract = "Major histocompatibility complex E (MHC-E) is a highly conserved, ubiquitously expressed, nonclassical MHC class Ib molecule with limited polymorphism that is primarily involved in the regulation of natural killer (NK) cells. We found that vaccinating rhesus macaques with rhesus cytomegalovirus vectors in which genes Rh157.5 and Rh157.4 are deleted results in MHC-E-restricted presentation of highly varied peptide epitopes to CD8αβ+ T cells, at ∼4 distinct epitopes per 100 amino acids in all tested antigens. Computational structural analysis revealed that MHC-E provides heterogeneous chemical environments for diverse side-chain interactions within a stable, open binding groove. Because MHC-E is up-regulated to evade NK cell activity in cells infected with HIV, simian immunodeficiency virus, and other persistent viruses, 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.",
author = "Hansen, {Scott G.} and Wu, {Helen L.} and Burwitz, {Benjamin J.} and Hughes, {Colette M.} and Hammond, {Katherine B.} and Ventura, {Abigail B.} and Reed, {Jason S.} and Gilbride, {Roxanne M.} and Emily Ainslie and Morrow, {David W.} and Ford, {Julia C.} and Selseth, {Andrea N.} and Reesab Pathak and Daniel Malouli and Legasse, {Alfred W.} and Axthelm, {Michael K.} and Nelson, {Jay A.} and Gillespie, {Geraldine M.} and Walters, {Lucy C.} and Simon Brackenridge and Sharpe, {Hannah R.} and L{\'o}pez, {C{\'e}sar A.} and Klaus Fr{\"u}h and Korber, {Bette T.} and McMichael, {Andrew J.} and S. Gnanakaran and Sacha, {Jonah B.} and Picker, {Louis J.}",
note = "Funding Information: We are grateful to T. van Hall for the HLA-E*01:03 transfectant; D. Geraghty for the 4D12 mAb; D. O{\textquoteright}Connor and R. Wiseman for 454-based MHC typing; and Y. Guo, D. Laddy, and M. Stone (Aeras) for provision of the 68-1 RhCMV construct expressing the M. tb. RpFA protein. We thank A. Townsend for help with the graphics; E. McDonald, A. Klug, A. Bhusari, G. Xu, J. Bae, C. Kahl, S. Hagen, A. Sylwester, and L. Boshears for technical or administrative assistance; J. Theiler for coding assistance; and P. Borrow for helpful discussions on HLA-E biology and peptide binding. This research was supported by NIH grants P01-AI094417, R37-AI054292, R01-DE021291, R01-AI095113, R01-AI117802, R01-AI059457, U24-OD010850, P51-OD011092, and P50-GM065794 and contract HHSN272201100013C; the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (grant UM1-AI100645-01) of the National Institute of Allergy and Infectious Diseases; the Bill and Melinda Gates Foundation (Global Health grants OPP1108533 and OPP1133649); the Aeras Global TB Vaccine Foundation; and the Center for Nonlinear Studies at the Los Alamos National Laboratory (LANL). LANL institutional computing was used for carrying out all-atom molecular dynamics simulations. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH or other funders. The Oregon Health and Science University (OHSU) has submitted a provisional patent entitled “Methods and compositions useful in generating non-canonical CD8+T cell responses” (inventors: L.J.P., K.F., J.B.S, D.M, and S.G.H.). OHSU and L.J.P., S.G.H., K.F., and J.A.N. have a substantial financial interest in TomegaVax, a company that may have a commercial interest in the results of this research and technology. L.J.P., K.F., and J.A.N. serve on the board of TomegaVax, and K.F. is also an uncompensated officer of the company. The potential individual and institutional conflicts of interest have been reviewed and managed by OHSU. Additional data used in this report are available as supplementary materials on Science Online. Publisher Copyright: {\textcopyright} 2016, American Association for the Advancement of Science. All rights reserved.",
year = "2016",
month = feb,
day = "12",
doi = "10.1126/science.aac9475",
language = "English (US)",
volume = "351",
pages = "714--720",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6274",
}