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© The Rockefeller University Press, 0022-1007/1999/10/1115/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 8, October 18, 1999 1115-1122

Original Article

Compromised Ox40 Function in Cd28-Deficient Mice Is Linked with Failure to Develop Cxc Chemokine Receptor 5–Positive Cd4 Cells and Germinal Centers

Lucy S.K. Walkera, Adam Gulbranson-Judgea, Sarah Flynna, Thomas Brockerb, Chandra Raykundaliaa, Margaret Goodalla, Reinhold Försterc, Martin Lippc, and Peter Lanea

a Department of Immunology, University of Birmingham Medical School, Birmingham B15 2TT, United Kingdom
b Max-Planck-Institute for Immunobiology, Freiburg D79108, Germany
c Max-Delbruck-Center for Molecular Medicine, Berlin D13122, Germany
Medical Research Council Centre for Immune Regulation, Birmingham Medical School, Vincent Dr., Birmingham B15 2TT, UK.44-121-414-359944-121-414-4078

p.j.l.lane{at}bham.ac.uk

Mice rendered deficient in CD28 signaling by the soluble competitor, cytotoxic T lymphocyte–associated molecule 4–immunoglobulin G1 fusion protein (CTLA4-Ig), fail to upregulate OX40 expression in vivo or form germinal centers after immunization. This is associated with impaired interleukin 4 production and a lack of CXC chemokine receptor (CXCR)5 on CD4 T cells, a chemokine receptor linked with migration into B follicles. Germinal center formation is restored in CTLA4-Ig transgenic mice by coinjection of an agonistic monoclonal antibody to CD28, but this is substantially inhibited if OX40 interactions are interrupted by simultaneous injection of an OX40-Ig fusion protein. These data suggest that CD28-dependent OX40 ligation of CD4 T cells at the time of priming is linked with upregulation of CXCR5 expression, and migration of T cells into B cell areas to support germinal center formation.

Key Words: CD28 • OX40/OX40 ligand • germinal center • chemokine • T cell migration

1used in this paper: CD11c-OX40L tg mice, transgenic mice expressing OX40L driven by the CD11c promoter; CTLA, CTL-associated molecule; CTLA4-Ig tg mice, transgenic mice expressing the soluble CD28 competitor, CTLA4-Ig; CXCR, CXC chemokine receptor; DC, dendritic cell; GC, germinal center; NP, 4-hydroxy-3-nitrophenyl acetyl; OX40-Ig, murine OX40–human IgG1 fusion protein; OX40L, OX40 ligand

© 1999 The Rockefeller University Press


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