PubMed ID
22206014
UMMS Affiliation
Department of Medicine, Division of Infectious Diseases and Immunology
Date
12-19-2011
Document Type
Article
Subjects
Adjuvants, Immunologic; Animals; CD4-Positive T-Lymphocytes; Dendritic Cells; Imidazoles; Interferon Type I; Interleukin-1alpha; Interleukin-1beta; Mice; Myeloid Differentiation Factor 88; Poly I-C; RNA; RNA, Messenger; Signal Transduction; Th1 Cells; Time Factors
Disciplines
Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences
Abstract
There is a growing need for novel vaccine adjuvants that can provide safe and potent T-helper type 1 (Th1) activity. RNA-like immune response modifiers (IRMs) are candidate T-cell adjuvants that skew acquired immune responses towards a Th1 phenotype. We set out to delineate the essential signaling pathways by which the RNA-like IRMs, resiquimod (R-848) and polyinosinic:polycytidylic acid (poly I:C), augment CD4+ T-helper 1 (Th1) responses. Highly purified murine conventional dendritic cells (cDCs) and conventional CD4+ T-cells were co-cultured in allogeneic and MHC congenic mixed leukocyte reactions. The activation of CD4+ Th1 cells was examined utilizing cells from mice deficient in specific RNA-sensing pattern recognition receptors and signaling mediators. R-848 and poly I:C stimulation of Type I interferon production and signaling in cDCs was essential but not sufficient for driving CD4+ Th1 responses. The early and rapid production of IL-1alpha and IL-1beta was equally critical for the optimal activation of Th1 CD4+ T-cells. R-848 activation of Toll-like receptor 7/MyD88-dependent signaling in cDCs led to a rapid upregulation of pro-IL-1alpha and pro-IL-1beta production compared to poly I:C activation of MyD88-independent signaling pathways. The in vitro data show that CD4+ T-cell adjuvant activity of RNA-like IRMs is mediated by a critical combination of early and rapid Type I interferon, IL-1alpha and IL-1beta production. These results provide important insights into the key signaling pathways responsible for RNA-like IRM CD4+ Th1 activation. A better understanding of the critical signaling pathways by which RNA-like IRMs stimulate CD4+ Th1 responses is relevant to the rational design of improved vaccine adjuvants.
Comments
Citation: Madera RF, Wang JP, Libraty DH (2011) The Combination of Early and Rapid Type I IFN, IL-1α, and IL-1β Production Are Essential Mediators of RNA-Like Adjuvant Driven CD4+ Th1 Responses. PLoS ONE 6(12): e29412. doi:10.1371/journal.pone.0029412. Link to article on publisher's site
Copyright: © 2011 Madera et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.