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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-¹

Suresh Radhakrishnan^*, Karla R. Wiehagen^*, Vesna Pulko^*, Virginia Van Keulen^*, William A. Faubion^*,, Keith L. Knutson^* and Larry R. Pease^2,*

^* Department of Immunology and Division of Gastroenterology, Department of Internal Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants CA96859, CA104996, and HL077296 (to L.R.P.) and DK64194 (to W.A.F.).

² Address correspondence and reprint requests to Dr. Larry R. Pease, Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. E-mail address: pease.larry{at}mayo.edu

³ Abbreviations used in this paper: DC, dendritic cell; CPG-ODN, CPG-containing oligodeoxynucleotide; int, intermediate; pI:C, polyinosinic:polycytidylic acid; SLAM, signaling lymphocytic activation module; XAb, cross-linking Ab.

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