TY - JOUR
T1 - Th-1 polarization is regulated by dendritic-cell comparison of MHC class I and class II antigens
AU - Decker, William K.
AU - Xing, Dongxia
AU - Li, Sufang
AU - Robinson, Simon N.
AU - Yang, Hong
AU - Steiner, David
AU - Komanduri, Krishna V.
AU - Shpall, Elizabeth J.
PY - 2009
Y1 - 2009
N2 - In the control of T-helper type I (Th-1) polarization, dendritic cells (DCs) 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 DCs with antigenically matched major histocompatibility complex (MHC) class I and class II determinants, that is, 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 13 independent antigenic models including whole-cell systems, single-protein systems, and 3 different pairs of overlapping class I and II binding epitopes. Once loaded with matched class I and II antigens, these "Th-1 DCs" exhibited differential cytokine secretion and surface marker expression, a distinct transcriptional signature, and acquired the ability to enhance 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 of more effective vaccination strategies.
AB - In the control of T-helper type I (Th-1) polarization, dendritic cells (DCs) 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 DCs with antigenically matched major histocompatibility complex (MHC) class I and class II determinants, that is, 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 13 independent antigenic models including whole-cell systems, single-protein systems, and 3 different pairs of overlapping class I and II binding epitopes. Once loaded with matched class I and II antigens, these "Th-1 DCs" exhibited differential cytokine secretion and surface marker expression, a distinct transcriptional signature, and acquired the ability to enhance 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 of more effective vaccination strategies.
UR - http://www.scopus.com/inward/record.url?scp=66149112867&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=66149112867&partnerID=8YFLogxK
U2 - 10.1182/blood-2008-10-185470
DO - 10.1182/blood-2008-10-185470
M3 - Article
C2 - 19171878
AN - SCOPUS:66149112867
SN - 1520-4391
VL - 113
SP - 4213
EP - 4223
JO - Unknown Journal
JF - Unknown Journal
IS - 18
ER -