A I Jaiswal | PubMed Health

PubMed1997

CD40 ligand induction on T cell subsets by peptide-presenting B cells: implications for development of the primary T and B cell response.

Recent data suggest that CD40 ligand (CD40L)-CD40 interactions are essential for up-regulation of costimulatory activity on APC and that efficient induction of CD40L may be pivotal to the success of a CD4 T cell response. CD40L is regulated primarily by TCR signaling, but high level expression on a naive T cell appears to require additional interactions between T cell coreceptors and APC accessory molecules. The data reported here show that resting B cells presenting peptide Ag, in contrast to both dendritic cells and preactivated B cells, induce very little CD40L on naive CD4 cells, which in turn is insufficient to promote APC costimulatory activity. We also show, however, that previously activated effector T cells have enhanced responsiveness to Ag when accessory molecule help is limiting and consequently can express high levels of CD40L after interaction with resting B cells. High level CD40L expression correlated with B cell activation and up-regulation of costimulatory activity; however, blocking studies showed that CD40L was only partially responsible for these phenomena. These studies reinforce the notion that resting B cells may be tolerogenic for naive CD4 cells in part because of inefficient CD40L induction. The data also suggest that a successful primary T cell response will only occur if either the initial interaction is with a dendritic cell followed by subsequent interactions of the effector T cells with resting APC or if nonspecific inflammatory stimuli up-regulate accessory molecule expression on resting APC before an encounter with the naive T cell.

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PubMed1996

Regulation of CD40 ligand expression on naive CD4 T cells: a role for TCR but not co-stimulatory signals.

We have investigated the roles of TCR and accessory co-stimulatory signals in the induction of CD40 ligand (CD40L) on CD4 cells. Using naive T cells form TCR transgenic mice, specific for a peptide of pigeon cytochrome c, we show that in contrast to IL-2 secretion, CD40L expression is regulated primarily by signalling through the TCR, is enhanced by accessory molecule interactions, but co-stimulatory signals play little if any role. CD40L was induced at high levels on naive T cells, peaking at 5 h, by class II MHC+ fibroblast antigen-presenting cells (APC) which expressed either ICAM-1, B7-1 or both molecules, whereas only low levels were induced by fibroblasts which did not express any accessory molecules. Differences in intensity and duration of expression were seen following stimulation with ICAM- and B7-expressing APC, with the presence of ICAM resulting in greater and longer expression, although both molecules together were most efficient. The involvement of co-stimulatory signals delivered from accessory molecules was investigated in systems where there was no effect on TCR signalling from adhesive interactions. Anti-CD3, or antigen-pulsed APC lacking accessory molecules, were used to provide the TCR signal, with co-stimulus from either anti-CD28 or accessory molecule-expressing fibroblasts not presenting antigen. Anti-CD3 in the absence of co-stimuli induced high CD40L expression but no IL-2 production and provision of co-stimulatory signals, although inducing large quantities of IL-2, did not increase CD40L expression. In addition, low CD40L expression induced by antigen presented in the absence of accessory molecules was not enhanced by co-stimulation, although IL-2 was strongly up-regulated. These studies suggest that efficient expression of CD40L on naive CD4 cells does require accessory molecules on APC. However, the role of these molecules for CD40L induction, as opposed to IL-2 secretion, is not one of co-stimulation but one of adhesion, presumably allowing stronger or more prolonged signals to be generated through the TCR. The synergistic role of ICAM and B7 during naive CD4 activation was confirmed using dendritic cells as APC, with nearly complete inhibition of CD40L expression as well as IL-2 secretion being seen when both CTLA-4-Ig and anti-LFA-1 were used to block these molecules.

Animals↗