CD4 T Cell Cytokine Differentiation: The B Cell Activation Molecule, OX40 Ligand, Instructs CD4 T Cells to Express Interleukin 4 and Upregulates Expression of the Chemokine Receptor, Blr-1

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J. Exp. Med., Volume 188, Number 2, July 20, 1998 297-304

CD4 T Cell Cytokine Differentiation: The B Cell Activation Molecule, OX40 Ligand, Instructs CD4 T Cells to Express Interleukin 4 and Upregulates Expression of the Chemokine Receptor, Blr-1

By Sarah Flynn, Kai-Michael Toellner, Chandra Raykundalia, Margaret Goodall, and Peter Lane

From the Department of Immunology, Birmingham Medical School, Birmingham B15 2TT, United Kingdom

This report investigates the role of OX40 ligand (OX40L) and its receptor, OX40, expressed on activated B and T cells, respectively,in promoting the differentiation of T helper type 2 (Th2) CD4T cells. These molecules are expressed in vivo by day 2 afterpriming with T cell- dependent antigens. Their expression coincideswith the appearance of immunoglobulin (Ig)G switch transcriptsand mRNA for interleukin (IL)-4 and interferon (IFN)- $gamma$ , suggestingthat this molecular interaction plays a role in early cognateinteractions between B and T cells. In vitro, we report that costimulationof naive, CD62L^high CD4 T cells through OX40 promotes IL-4 expression and upregulatesmRNA for the chemokine receptor, blr-1, whose ligand is expressedin B follicles and attracts lymphocytes to this location. Furthermore,T cell stimulation through OX40 inhibits IFN- $gamma$ expression in bothCD8 T cells and IL-12-stimulated CD4 T cells. Although this signalinitiates IL-4 expression, IL-4 itself is strongly synergistic.Our data suggest that OX40L on antigen-activated B cells instructsnaive T cells to differentiate into Th2 cells and migrate intoB follicles, where T cell-dependent germinal centers develop.

Key words: Th1-Th2 differentiation; OX40/OX40 ligand; cytokine; T cell priming; cognate B cell-T cell interaction

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