Submitted October 29, 2008
Accepted January 18, 2009
Th-1 polarization is regulated by dendritic cell comparison of MHC class I and class II antigens
William K. Decker*, Dongxia Xing, Sufang Li, Simon N. Robinson, Hong Yang, David Steiner, Krishna V. Komanduri, and Elizabeth J. Shpall
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: wkdecker{at}mdanderson.org.
In the control of Th-1 polarization and generation of CD8+ responses, dendritic cells (DC) must interpret a complex array of stimuli, many of which are poorly understood. Here we demonstrate that Th-1 polarization is heavily influenced by DC-autonomous phenomena triggered by the loading of DC with antigenically matched MHC class I and class II determinants, i.e. class I and II peptide epitopes exhibiting significant amino acid sequence overlap (such as would be physiologically present during infectious processes requiring Th-1 immunity for clearance). Data were derived from thirteen independent antigenic models including whole-cell systems, single protein systems, and three different pairs of overlapping class I and II binding epitopes. Once loaded with matched class I and II antigens, these "Th-1 DC" exhibited differential cytokine secretion and surface marker expression, a distinct transcriptional signature, and acquired the ability to enhance the generation of CD8+ T-lymphocytes. Mechanistically, tRNA-synthetases were implicated as components of a putative sensor complex involved in the comparison of class I and II epitopes. These data provide rigorous conceptual explanations for the process of Th-1 polarization and the antigenic specificity of cognate T-cell help, enhance the understanding of Th-1 responses, and should contribute to the formulation more effective vaccination strategies.
