Induction of a Th1 Response from Th2-Polarized T Cells by Activated Dendritic Cells: Dependence on TCR:Peptide-MHC Interaction, ICAM-1, IL-12, and IFN-γ

Abstract

Dendritic cells (DC) are important regulators of T cell immunity. The degree of stimulation, the pattern of costimulatory molecules expressed, and the cytokines secreted by DC dictate the nature of the effector and memory cells generated, particularly with respect to their Th1 or Th2 phenotypes. In this study, we demonstrate that the addition of activated DC to spleen cultures containing established Th2-polarized CD4+ T cells was sufficient to suppress Th2 and induce Th1 cytokines in a recall response, a phenomenon referred to as phenotype reversal. The ability of activated DC to induce phenotype reversal displayed exquisite Ag specificity. The DC activator B7-DC cross-linking Ab (XAb) was >10,000-fold more efficient at inducing phenotype reversal than the TLR agonists CpG-oligodeoxynucleotide and Gardiquimod. Characterization of the mechanisms governing phenotype reversal revealed the requirement for cognate interaction between the TCR:peptide-MHC complex, the expression of the costimulation/adhesion molecule ICAM-1, and secretion of IL-12 and IFN-γ by the activated DC. The requirement for the costimulation/adhesion molecule SLAM (signaling lymphocytic activation molecule) was found to be quantitative. Thus, activation of DC, particularly by crosslinking B7-DC, can modulate well-established Th2 T cell responses in an Ag-specific manner. Because the regulation of mouse and human DC by B7-DC XAb overlaps in several significant ways, immune modulation with B7-DC XAb is a potential strategy for treating Th2-mediated diseases.

IFN-γ, as Secreted during an Alloresponse, Induces Differentiation of Monocytes into Tolerogenic Dendritic Cells, Resulting in FoxP3+ Regulatory T Cell Promotion

“…Tol-DC induce immune tolerance through several pathways, including clonal depletion of alloreactive T lymphocytes, anergy, deviation of Th differentiation, or generation of Treg (19,20 can express both IL-10 and FoxP3 cells (29). In our study, we detected increased expression of FoxP3 and IL-10, but not TGF␤ mRNA, by T cells primed with mmCFS-DC following secondary stimulation with donor APC (Fig.…”

Upregulation of stress-response genes with cell cycle arrest induced by carbon ion irradiation in multiple murine tumors models

“…In addition, C-ion exposure induced the expression of the adhesion-related gene, Icam1, and the costimulatory effect mediated by ICAM-1 expression is necessary for the activation of cytotoxic T lymphocytes. 35 These data provide an explanation for the increased immunogenicity of tumors and suggest that the enhanced immune recognition in the irradiated tumor contributes to the efficacy of this modality. The results of the present study also support a role for local therapy as a powerful biological modifier.…”

β-Defensin-2 Promotes Resistance against Infection with P. aeruginosa

“…IFN-␥ is an important regulatory cytokine that plays a critical role in inflammation and Th1 responses (35,36), MyD88 is a key adaptor molecule in all TLR signaling pathways except for TLR3 (37,38), and NF-B is the transcription factor in all TLR/MyD88-dependent signaling pathways whose activation leads to inflammatory cytokine production (38,39). Thus, their up-regulation (peaking at 3 days p.i.)…”