The biological outcome of CD40 signaling is dependent on the duration of CD40 ligand expression: reciprocal regulation by interleukin (IL)-4 and IL-12.
Bottom Line: IL-4 represses, whereas IL-12 sustains CD154 expression.Consistent with this, Th1, but not Th2, cells express CD154 for extended periods.Thus, the differential ability of Th cells to sustain CD154 expression is an important part of their helper function and should influence the activities of other CD40-expressing cell types.
Affiliation: Trudeau Institute, Saranac Lake, NY 12983, USA.
CD40 ligand (CD154) expression on activated T cells can be separated into an early TCR-dependent phase, which occurs between 0 and 24 h after activation, and a later extended phase, which occurs after 24 h and is reciprocally regulated by the cytokines IL-4 and IL-12. IL-4 represses, whereas IL-12 sustains CD154 expression. Consistent with this, Th1, but not Th2, cells express CD154 for extended periods. Differences in the duration of CD154 expression have important biological consequences because sustained, but not transient, expression of CD154 on activated T cells can prevent B cell terminal differentiation. Thus, the differential ability of Th cells to sustain CD154 expression is an important part of their helper function and should influence the activities of other CD40-expressing cell types.
Mentions: To determine whether cytokines played a role in regulating the first or second phases of CD154 expression on activated T cells, purified naive AND T cells were stimulated with CH12 cells and PCCF in the presence of a variety of cytokines, and the kinetics of CD154 expression were followed over 72 h. We found that IL-2, IL-5, IL-6, IL-10, IL-13, and IFN-γ had no effect on either the levels or kinetics of CD154 expression (unpublished data). However, both IL-4 and IL-12 influenced the second phase of CD154 in the model of cognate T–B interaction (Fig. 2 A). Although IL-12 had minimal effect on the level of CD154 expression on peptide-stimulated T cells at 6 h, IL-4 slightly, but consistently, increased the percentage of cells expressing CD154 at this time (Fig. 2 A). Similar to what we observed in Fig. 1 B, there was a dramatic decrease in CD154 expression on T cells stimulated with peptide-presenting CH12 cells for 24 h, regardless of cytokine addition (Fig. 2 A). In striking contrast, however, the second phase of CD154 expression at 48 and 72 h was completely absent on T cells cultured with IL-4, whereas the second phase of CD154 expression remained elevated for extended periods on T cells cultured with IL-12 (Fig. 2 A). Furthermore, the inhibitory effects of IL-4 were dominant over the effects of IL-12 as T cells stimulated in the presence of both cytokines expressed CD154 in a pattern identical to that on T cells stimulated in the presence of IL-4 alone (Fig. 2 A). Similar results were seen using OTII transgenic T cells and with normal T cells (not depicted).