In a recent report in Blood, Cohen et al. indicate that the transcription factor glucocorticoid-induced leucine zipper (GILZ) has a crucial role in determining whether dendritic cells (DCs) stimulate or tolerize T cells. Moreover, it provides a common mechanism for the inhibition of DC maturation by interleukin-10 (IL-10) and glucocorticoids.

expression of GILZ by DCs treated with dexamethasone or IL-10 prevented them from stimulating T-cell proliferation

Optimal activation of T cells requires interaction between the co-stimulatory molecules CD80 and CD86 (expressed by DCs) and CD28 (expressed by T cells). By contrast, anergy or tolerance of T cells might be induced by interaction with immature DCs, which do not express these co-stimulatory molecules, but do express tolerance-inducing molecules such as IL-10, B7-H1 and immunoglobulin-like transcript 3 (ILT3). This tolerogenic DC phenotype can be induced by exposure of DCs to IL-10, glucocorticoids or transforming growth factor-β (TGFβ). As its name suggests, GILZ expression is induced in DCs in response to glucocorticoids, as well as IL-10. So, the authors asked whether the induction of GILZ expression by DCs could explain the inhibitory effect of glucocorticoids and IL-10 on immune responses.

First, the authors confirmed that treatment of monocyte-derived human DCs with IL-10 or dexamethasone (a synthetic glucocorticoid) resulted in induction of GILZ expression, and inhibited the expression of CD80 and CD86 but stimulated expression of B7-H1. Importantly, knockdown of GILZ gene expression, using small interfering RNA (siRNA), prevented the IL-10- or dexamethasone-induced phenotypic changes, whereas transfection of DCs with GILZ was sufficient to cause these changes.

In addition to modulating the phenotype of DCs, GILZ also affected their function. GILZ expression stimulated the production of IL-10 by DCs to the same extent as that achieved with dexamethasone, and it could inhibit chemokine production induced by CD40 ligand (CD40L). However, GILZ expression did not prevent all of the consequences of DC maturation, as it did not affect CD40L-induced inhibition of phagocytosis.

Consistent with its effect on DC maturation, the authors next showed that the expression of GILZ by DCs treated with dexamethasone or IL-10 prevented them from stimulating T-cell proliferation and interferon-γ release. Knockdown of GILZ with siRNA abolished this effect and restored a strong T-cell proliferative response.

Given that glucocorticoids are widely used to treat immune disorders that involve uncontrolled immune activation, the authors tested whether GILZ might be important for their mechanism of action. Indeed, GILZ expression was induced in circulating monocytes that were isolated from patients treated with glucocorticoids, and this impaired the ability of these cells to stimulate T cells.

So, a role for GILZ seems to be a common feature of immune control mediated by IL-10 and glucocorticoids, adding another level to our understanding of how DCs regulate adaptive immune responses.