MHC class I and II peptide homology regulates the cellular immune response

Mammalian immune responses are initiated by “danger” signals––immutable molecular structures known as PAMPs. When detected by fixed, germline encoded receptors, pathogen‐associated molecular pattern (PAMPs) subsequently inform the polarization of downstream adaptive responses depending upon identity...

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Bibliographic Details
Published in:The FASEB journal 2020-06, Vol.34 (6), p.8082-8101
Main Authors: Halpert, Matthew M., Konduri, Vanaja, Liang, Dan, Vazquez‐Perez, Jonathan, Hofferek, Colby J., Weldon, Scott A., Baig, Yunyu, Vedula, Indira, Levitt, Jonathan M., Decker, William K.
Format: Article
Language:English
Subjects:
AIMp1
Amino Acid Sequence - physiology
Amino Acyl-tRNA Synthetases - immunology
Animals
CTLA‐4
dendritic cell
Dendritic Cells - immunology
Histocompatibility Antigens Class I - immunology
Histocompatibility Antigens Class II - immunology
Immunity, Cellular - immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
PAMP
Peptides - immunology
PRR
Th1 Cells - immunology
TH1 polarization
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Summary:Mammalian immune responses are initiated by “danger” signals––immutable molecular structures known as PAMPs. When detected by fixed, germline encoded receptors, pathogen‐associated molecular pattern (PAMPs) subsequently inform the polarization of downstream adaptive responses depending upon identity and localization of the PAMP. Here, we report the existence of a completely novel “PAMP” that is not a molecular structure but an antigenic pattern. This pattern––the incidence of peptide epitopes with stretches of 100% sequence identity bound to both dendritic cell (DC) major histocompatibility (MHC) class I and MHC class II––strongly induces TH1 immune polarization and activation of the cellular immune response. Inherent in the existence of this PAMP is the concomitant existence of a molecular sensor complex with the ability to scan and compare amino acid sequence identities of bound class I and II peptides. We provide substantial evidence implicating the multienzyme aminoacyl‐tRNA synthetase (mARS) complex and its AIMp1 structural component as the key constituents of this complex. The results demonstrate a wholly novel mechanism by which T‐helper (TH) polarization is governed and provide critical information for the design of vaccination strategies intended to provoke cell‐mediated immunity.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.201903002R