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

Abstract

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.

Role of Ox40 Signals in Coordinating Cd4 T Cell Selection, Migration, and Cytokine Differentiation in T Helper (Th)1 and Th2 Cells

“…Constitutive expression of OX40L on DCs leads to a CD28-dependent increase in the numbers of CXCR-5 CD4 cells 5, greatly increased numbers of CD4 T cells within B follicles, and large GCs 3. Preliminary analysis of OX40-deficient mice shows the opposite phenotype, with GC formation being reduced (unpublished observations).…”

“…In contrast, expression of the T cell activation antigen OX40 on naive CD4 T cells is largely CD28 dependent, both in vivo and in vitro 5. Although others have suggested that OX40 expression is CD28 independent 6, these studies looked at total rather than naive CD4 T cell responses.…”

“…A key point concerning recall CD4 responses is that most primed CD4 cells are located in B follicles and GCs by day 10. Signaling through CD28 and OX40 upregulates mRNA for CXCR-5 in vitro 4, and CD28 signaling is required to generate the CXCR-5 subset of memory CD4 T cells in vivo 5. The lack of CXCR-5–positive CD4 T cells in CD28-deficient mice is directly correlated with their failure to form GCs 16.…”

Both the pre-BCR and the IL-7Rα are essential for expansion at the pre-BII cell stagein vivo

“…Cell numbers were calculated based on the proportion of viable cells in the lymphocyte gate using, where possible, propidium iodide (0.25 lg/ml) to exclude dead cells. Tissue sections were double-stained for IgD (Binding Site) in combination with either IgM (Serotec), CD3 (KT3; Serotec) or CD4 (GK1.5; Serotec) as described [48].…”

The role of the T follicular helper cells in allergic disease

“…[3][4][5] These were first termed T follicular helper (Tfh) cells by Chtanova et al 6 Germinal centre localized Tfh cells expressed the chemokine receptor CXCR5 as well as costimulatory molecules CD40L 7 and ICOS. 8 IL-21 is required for germinal centre formation for T-cell dependent antigens.…”