Th-1 polarization is regulated by dendritic-cell comparison of MHC class I and class II antigens.
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.
Decker
William K
WK
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA. wkdecker@mdanderson.org
Xing
Dongxia
D
Li
Sufang
S
Robinson
Simon N
SN
Yang
Hong
H
Steiner
David
D
Komanduri
Krishna V
KV
Shpall
Elizabeth J
EJ
D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism; D017951:Antigen Presentation; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000097802:CD83 Antigen
D000604:Amino Acyl-tRNA Synthetases; D015703:Antigens, CD; D015415:Biomarkers; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins; D007371:Interferon-gamma; D018664:Interleukin-12; D008562:Membrane Glycoproteins; D000097802:CD83 Antigen