Compromised OX40 Function in CD28-deficient Mice Is Linked with Failure to Develop CXC Chemokine Receptor 5-positive CD4 Cells and Germinal Centers

doi:10.1084/jem.190.8.1115

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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

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. Walker^a, Adam Gulbranson-Judge^a, Sarah Flynn^a, Thomas Brocker^b, Chandra Raykundalia^a, Margaret Goodall^a, Reinhold Förster^c, Martin Lipp^c, and Peter Lane^a
^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

Correspondence to: Peter Lane, Medical Research Council Centre for Immune Regulation, Birmingham Medical School, Vincent Dr., Birmingham B15 2TT, UK. Tel:44-121-414-4078 Fax:44-121-414-3599 E-mail:p.j.l.lane{at}bham.ac.uk.

Mice rendered deficient in CD28 signaling by the soluble competitor,cytotoxic T lymphocyte–associated molecule 4–immunoglobulinG1 fusion protein (CTLA4-Ig), fail to upregulate OX40 expressionin vivo or form germinal centers after immunization. This isassociated with impaired interleukin 4 production and a lackof CXC chemokine receptor (CXCR)5 on CD4 T cells, a chemokinereceptor linked with migration into B follicles. Germinal centerformation is restored in CTLA4-Ig transgenic mice by coinjectionof an agonistic monoclonal antibody to CD28, but this is substantiallyinhibited if OX40 interactions are interrupted by simultaneousinjection of an OX40-Ig fusion protein. These data suggest thatCD28-dependent OX40 ligation of CD4 T cells at the time of primingis linked with upregulation of CXCR5 expression, and migrationof T cells into B cell areas to support germinal center formation.

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

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