IDO expands human CD4⁺CD25^high regulatory T cells by promoting maturation of LPS‐treated dendritic cells

Abstract

We have previously shown that human monocyte-derived dendritic cells (DC) express indoleamine 2,3-dioxygenase (IDO), as well as several other enzymes of the kynurenine pathway at the mRNA level upon maturation. The tolerogenic mechanisms of this pathway remain unclear. Here we show that LPS-treated DC metabolize tryptophan as far as quinolinate. We found that IDO contributes to LPS and TNF-a + poly(I:C)-induced DC maturation since IDO inhibition using two different inhibitors impairs DC maturation. IDO knock-down using short-hairpin RNA also led to diminished LPSinduced maturation. In line with these results, the tryptophan-derived catabolites 3-hydroxyanthranilic acid and 3-hydroxykynurenine increased maturation of LPStreated DC. Concerning the molecular mechanisms of this effect, IDO acts as an intermediate pathway in LPS-induced production of reactive oxygen species and NF-jB activation, two processes that lead to DC maturation. Finally, we show that mature DC expand CD4 + CD25 high regulatory T cells in an IDO-dependent manner. In conclusion, we show that IDO constitutes an intermediate pathway in DC maturation leading to expansion of CD4 + CD25 high regulatory T cells.

Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase

“…Also, our finding that dLN pDCs from mice treated with D-1MT and PMA did not exhibit T cell suppressor activity when D-1MT was absent from ex vivo cultures suggests that the pDCs may have undergone irreversible differentiation to acquire T cell stimulatory functions in the absence of IDO activity in vivo, so that pDCs were unable to recover suppressor activity ex vivo even when IDO inhibitor was no longer present. Indeed, a role for IDO in regulating maturation of human DCs has recently been reported (33).…”

Tryptophan Deprivation Induces Inhibitory Receptors ILT3 and ILT4 on Dendritic Cells Favoring the Induction of Human CD4+CD25+ Foxp3+ T Regulatory Cells

“…It has been suggested that a portion of Tregs is derived from rapidly dividing peripheral memory CD4 ϩ CD45RO ϩ T cells or from activated CD4 ϩ T cells by Ag stimulation (52,53). Recently, Hill et al (54) found that IDO enzymatic activity in LPS-stimulated DCs contributes to the expansion of Tregs. Furthermore, it is known that the IDO pathway itself is able to induce the differentiation of naive CD4…”

Intralesional Regulatory T-Cell Suppressive Function during Human Acute and Chronic Cutaneous Leishmaniasis Due to Leishmania guyanensis

“…ϩ T cells (11,16), and tryptophan metabolites were shown to enhance the expression of the Foxp3-encoding gene (12). Thus, we cannot exclude that tryptophan metabolites induced by IDO activation could results in Treg cell activation.…”