T-bet expression by dendritic cells is required for the repolarization of allergic airway inflammation.
By cross-linking B7-DC on dendritic cells (DC) the human IgM antibody (B7-DC XAb) shifts polarized immune responses from Th2 to Th1 in an antigen-specific manner. The molecular determinants governing the ability of DC to reprogram the polarity of T cell recall responses are not yet known. In addition to the expected role of T-bet expressed by T cells in regulating Th1 responses, we find using in vitro assays and an established in vivo model of allergic airway inflammation that T-bet expression by DC is also required for the polarity shift promoted by B7-DC XAb. T-bet expression by both T cells and DC is critically important for B7-DC XAb-induced down-regulation of IL-4, up-regulation of IFN-gamma and suppression of allergic airway inflammation. Moreover, retroviral reconstitution of T-bet expression in T-bet-deficient DC rescued their ability to modulate both naive and memory T-cell responses from Th2 to Th1. Our observations further our understanding of the critical mediators controlling the ability of DC to modify the responses of previously activated T cells and reveal the interesting use of the same transcription factor to regulate the inductive phenotype of DC and the inducible phenotype of T cells.
Heckman
Karin L
KL
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Radhakrishnan
Suresh
S
Peikert
Tobias
T
Iijima
Koji
K
McGregor
Hugh C
HC
Bell
Michael P
MP
Kita
Hirohito
H
Pease
Larry R
LR
D019264:Adoptive Transfer; D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D016764:Cell Polarity; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D061027:Programmed Cell Death 1 Ligand 2 Protein; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation; D000098815:T-bet Transcription Factor
D018122:B7-1 Antigen; C556977:PDCD1LG2 protein, human; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin