Edited by Hidde L. Ploegh, Boston Children’s Hospital, Boston, MA, and approved January 8, 2019 (received for review April 30, 2018)
Provision of sufficient activating signals can drive self-tolerant T cells to cross-react on self-peptide-MHC in a breakdown of tolerance. This approach has been applied in the development of heteroclitic peptide vaccines, which retain sufficient similarity to self to allow reactivation of effector cells on unaltered self-epitopes but require detailed knowledge about the behavior of individual altered self-peptide antigens. We designed altered-self MHC mutant antigen-presenting molecules to drive CTL capable of cross-reacting on self-peptide-MHC and demonstrate the breaking of self-tolerance to defined and undefined self-antigens. These findings bear particular importance in the field of cancer immunotherapy in which breaking tolerance to weakly antigenic cancer-associated antigens is fundamental to vaccination strategies.
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.
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.
Conflict of interest statement: The authors have a pending US patent application, US20160361402A1, relevant to the delivery of MHC class I heavy chain mutant genes using adenoviral transduction in humans.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1807465116/-/DCSupplemental.
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