Breaking tolerance with engineered class I antigen-presenting molecules
Successful efforts to activate T cells capable of recognizing weak cancer-associated self-antigens have employed altered peptide antigens to activate T cell responses capable of cross-reacting on native tumor-associated self. A limitation of this approach is the requirement for detailed knowledge ab...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 8; pp. 3136 - 3145 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
19.02.2019
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Series | PNAS Plus |
Subjects | |
Online Access | Get full text |
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Summary: | Successful efforts to activate T cells capable of recognizing weak cancer-associated self-antigens have employed altered peptide antigens to activate T cell responses capable of cross-reacting on native tumor-associated self. A limitation of this approach is the requirement for detailed knowledge about the altered self-peptide ligands used in these vaccines. In the current study we considered allorecognition as an approach for activating CTL capable of recognizing weak or self-antigens in the context of self-MHC. Nonself antigen-presenting molecules typically contain polymorphisms that influence interactions with the bound peptide and TCR interface. Recognition of these nonself structures results in peptide-dependent alloimmunity. Alloreactive T cells target their inducing alloantigens as well as third-party alloantigens but generally fail to target self-antigens. Certain residues located on the alpha-1/2 domains of class I antigen-presenting molecules primarily interface with TCR. These residues are more conserved within and across species than are residues that determine peptide antigen binding properties. Class I variants designed with amino acid substitutions at key positions within the conserved helical structures are shown to provide strong activating signals to alloreactive CD8 T cells while avoiding changes in naturally bound peptide ligands. Importantly, CTL activated in this manner can break self-tolerance by reacting to self-peptides presented by native MHC. The ability to activate self-tolerant T cells capable of cross-reacting on self-peptide-MHC in vivo represents an approach for inducing autoimmunity, with possible application in cancer vaccines. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: C.A.P., K.D.P., V.P.V.K., B.K.R., A.G.S., D.G., A.J.B., M.A.B., and L.R.P. designed research; C.A.P., K.R.H., M.J.H., V.P.V.K., B.K.R., and A.J.B. performed research; J.D.S., A.G.S., D.G., D.M.K., A.J.B., and M.A.B. contributed new reagents/analytic tools; C.A.P., V.P.V.K., B.K.R., A.J.B., and L.R.P. analyzed data; and C.A.P. and L.R.P. wrote the paper. Edited by Hidde L. Ploegh, Boston Children’s Hospital, Boston, MA, and approved January 8, 2019 (received for review April 30, 2018) |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1807465116 |