Halpert et al. presented evidence of a novel PAMP that is not a molecular structure, but rather a pattern of high antigenic homology between intracellular and extracellular environments. The researchers presented evidence that in DCs, the mARs complex acts as a sensor capable of scanning and comparing amino acid sequences of peptides loaded onto MHC-I and MHC-II, and that when homology is detected, AIMp1 dissociates from the complex, lowering the release of inhibitory CTLA-4-containing microvesicles from DCs, inducing a cDC1 phenotype, and triggering downstream Th1 cellular responses, including CD8+ T cell responses.
Contributed by Lauren Hitchings
ABSTRACT: 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 TH 1 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.
Author Info: (1) Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. (2) Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. (3)
Author Info: (1) Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. (2) Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. (3) Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. (4) Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. (5) Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. (6) Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA. (7) Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. (8) Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. (9) Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. (10) Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
