Interleukin-4 acts at the locus of the antigen-presenting dendritic cell to counter-regulate cytotoxic CD8+ T-cell responses

Abstract

The mechanism underlying suppression of immune responses by interleukin-4 (IL-4) has remained unexplained. Here we show that the antigen-presenting dendritic cell is central to counter-regulation of autoimmune disease by IL-4. IL-4 acts at the locus of the dendritic cell to decrease the cytolytic T-cell response, preventing autoimmunity. Stimulation of cytotoxic precursors by antigen pulsed dendritic cells induces their differentiation but the process is blocked by IL-4. IL-4-influenced DC produce distinct effects on CD8+ T cells depending on their state of activation. The molecular basis for this regulation is the alteration of the expression ratio of the costimulatory ligands B7.1/B7.2 on dendritic cells. Our findings demonstrate that B7.2 induces expansion of CD8+ T cells and B7.1 governs their acquisition of cytolytic activity. IL-4 influences the dendritic cell to elicit qualitative differences in T-cell responses, providing the basis for counter-regulation mediated by IL-4.

Reduced antigen concentration and costimulatory blockade increase IFN‐γ secretion in naive CD8+ T cells

“…Consistent with our findings, a number of other groups have reported that IL-4 DC generate a stronger cytolytic response compared to DC generated with GM-CSF alone [18,35,36]. Despite this difference, our data and the data from King et al [20] show that IL-4 exerts immunoregulatory effects by preconditioning the DC to alter their composition of costimulatory molecules [20].…”

“…We also found that IL-4 promoted the acquisition of cytolytic capacity in the T cells. King et al [20] found the opposite. It is possible that in vivo, IL-4 would affect also other cells than DC that might reduce the cytotoxic potential.…”

“…Mouse GM-CSF DC produce IFN-a/b [32], which could directly trigger IFN-c secretion in virusspecific CD8 + T cells [33]. An interesting possibility that remains to be tested is that IL-4 would down-modulate Previous work has suggested that the B7.1/B7.2 ratio on APC is an important factor that regulates IFN-c secretion in CD8 + T cells [20]. In this study, B7.1 and B7.2 both provided a down-regulatory signal for IFN-c expression, arguing against the ratio as a critical factor in our model.…”

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

“…Several mechanisms of action have been suggested in the past [6,7,35] for the effect of DC and/or IL-4 in NOD mice. We opted for a different approach, using microarray analysis, to get a broader picture of the impact of DC/IL-4 treatment on gene expression in targeted tissues.…”

“…IL-4 may be important in the maintenance of a protective Th2 response [5], but it has also been implicated in the stimulation of a broader T cell repertoire composed of non-pathogenic cells [6] and in differential expression of B7.1 and B7.2 molecules by DCs, affecting the quality of CTL responses [7]. Systemic administration of IL-4 appeared to alleviate a form of unresponsiveness among NOD thymocytes and peripheral T cells, which correlated with disease protection [8].…”