TY - JOUR
T1 - Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources
AU - Kim, Aeryon
AU - Hartman, Isamu Z.
AU - Poore, Brad
AU - Boronina, Tatiana
AU - Cole, Robert N.
AU - Song, Nianbin
AU - Ciudad, M. Teresa
AU - Caspi, Rachel R.
AU - Jaraquemada, Dolores
AU - Sadegh-Nasseri, Scheherazade
N1 - Funding Information:
S.S.-N. and A.K. wish to dedicate this paper to the memory of late Eli Sercarz who proposed the ‘determinant capture’ theory. We thank Drs Emil Unanue and Lawrence Stern for reading of the manuscript and discussions and the gift of anti DR Ab, Champ2. This work was supported by grants from NIAID (R01AI063764, R21 AI101987) and NIGM (GM053549), a pilot grant from Johns Hopkins Malaria Research Institute to S.S.-N., a Johns Hopkins University Rheumatology T32, a Graduate Immunology T32 Fellowship to A.K. and a National Science Foundation predoctoral student award to I.Z.H. M.T.C. and D.J. were supported by a grant, SAF2009-10622 from the Spanish Ministry of Science to D.J. and the F.P.I. fellowship BES2001-03963 to M.T.C. We wish to thank our colleagues in the Department of Pathology, Drs Hui Zhang and Punit Sha for peptide sequence identification shown in Supplementary Figures 5–8 and Dr Daniela Cihakova, JHU Pathology Department, for the gift of myosin peptide, and Mary J Mattapallil for uveitis peptide. BEI resources provided influenza recombinant proteins and NIAID Tetramer Facility for DR3 and DR4 monomers, Dr Dennis Zaller, MERCK, provided the original HLA-DR1 Tg mice.
Publisher Copyright:
© 2014 Macmillan Publishers Limited. All rights reserved.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - Immunodominant epitopes are few selected epitopes from complex antigens that initiate T-cell responses. Here to provide further insights into this process, we use a reductionist cell-free antigen-processing system composed of defined components. We use the system to characterize steps in antigen processing of pathogen-derived proteins or autoantigens and we find distinct paths for peptide processing and selection. Autoantigen-derived immunodominant epitopes are resistant to digestion by cathepsins, whereas pathogen-derived epitopes are sensitive. Sensitivity to cathepsins enforces capture of pathogen-derived epitopes by major histocompatibility complex class II (MHC class II) before processing, and resistance to HLA-DM-mediated-dissociation preserves the longevity of those epitopes. We show that immunodominance is established by higher relative abundance of the selected epitopes, which survive cathepsin digestion either by binding to MHC class II and resisting DM-mediated-dissociation, or being chemically resistant to cathepsins degradation. Non-dominant epitopes are sensitive to both DM and cathepsins and are destroyed.
AB - Immunodominant epitopes are few selected epitopes from complex antigens that initiate T-cell responses. Here to provide further insights into this process, we use a reductionist cell-free antigen-processing system composed of defined components. We use the system to characterize steps in antigen processing of pathogen-derived proteins or autoantigens and we find distinct paths for peptide processing and selection. Autoantigen-derived immunodominant epitopes are resistant to digestion by cathepsins, whereas pathogen-derived epitopes are sensitive. Sensitivity to cathepsins enforces capture of pathogen-derived epitopes by major histocompatibility complex class II (MHC class II) before processing, and resistance to HLA-DM-mediated-dissociation preserves the longevity of those epitopes. We show that immunodominance is established by higher relative abundance of the selected epitopes, which survive cathepsin digestion either by binding to MHC class II and resisting DM-mediated-dissociation, or being chemically resistant to cathepsins degradation. Non-dominant epitopes are sensitive to both DM and cathepsins and are destroyed.
UR - http://www.scopus.com/inward/record.url?scp=84920649458&partnerID=8YFLogxK
U2 - 10.1038/ncomms6369
DO - 10.1038/ncomms6369
M3 - Article
C2 - 25413013
SN - 2041-1723
VL - 5
JO - Nature Communications
JF - Nature Communications
M1 - 5369
ER -