Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase

Abstract

Murine dendritic cells (DCs) expressing indoleamine 2,3 dioxygenase (IDO) catabolize tryptophan and can suppress T cell responses elicited in vivo. Here, we identify specific subsets of splenic (CD11c+) dendritic cells competent to mediate IDO-dependent T cell suppression following CTLA4-mediated ligation of B7 molecules. IDO-competent DC subsets acquired potent and dominant T cell suppressive properties as a consequence of IDO up-regulation, as they blocked the ability of T cells to respond to other stimulatory DCs in the same cultures. Soluble CTLA4 (CTLA4-Ig) and cloned CTLA4+ regulatory T cells (Tr1D1) up-regulated IDO selectively in DC subsets co-expressing B220 or CD8alpha. The ability of Tr1D1 T cells to suppress CD8+ T cell responses was completely dependent on their ability to induce tryptophan catabolism in DCs. Selective IDO up-regulation in DCs did not inhibit T cell activation, but prevented T cell clonal expansion due to rapid death of activated T cells. T cell responses were restored by genetic or pharmacologic inhibition of IDO enzyme activity, or by adding excess tryptophan. DCs from interferon gamma (IFNgamma)-receptor-deficient mice were effective in promoting IDO-dependent T cell suppression following CTLA4-Ig exposure in vivo, indicating that IFNgamma signaling was not necessary for IDO up-regulation in this model. These findings suggest that IDO-competent DCs provide a regulatory bridge, mediated by CTLA4-B7 engagement, between certain regulatory T cell subsets and naive responder T cells.

Systemic application of CpG‐rich DNA suppresses adaptive T cell immunity via induction of IDO

“…3B). Systemic CpG-ODN administration induces IDO expression in the spleen It has been reported that activation of the enzyme IDO can inhibit T cell proliferation via depletion of tryptophan and/or via generation of suppressive tryptophan cleavage products [19,20]. We investigated whether the suppressive effect of systemic CpG-ODN application on T cell expansion is linked to IDO activity.…”

“…T cell suppression by systemic CpG-ODN treatment is mediated by IDO activity For investigation of the functional relevance of IDO expression, the tryptophan analogue 1-methyl-tryptophan (1-MT), a well-established competitive inhibitor of IDO [19,20,22], was used. OVA-induced proliferation of CFSE-labeled OT-I cells was blocked by the presence of CpG-ODN in in vitro culture (Fig.…”

Tolerogenicity is not an absolute property of a dendritic cell

“…The modulated BMDC populations were clearly not refractory to LPS stimulation, but instead retained much of the normal LPSinduced transcription response. While some maturation of adoptively transferred tolerogenic DC is required to promote migration to the lymph nodes for Ag presentation to T cells [28], transcripts increased in response to LPS in this study encoded both classic proinflammatory agents, such as IL-1 and NOS2, and also well-characterized inhibitory molecules, such as IL-10, Indo and CD274 (PD-L1) [12,16,29] (Supporting Information Fig. 2A).…”

“…Numerous studies linking tolerance to DC maturation status have emphasized the importance of incomplete signaling to T cells [4][5][6][7][8], while others have highlighted dominant interactions delivering negative or co-inhibitory signals as critical [11][12][13][14]16]. More complete explanations advocate some balance of the two, with micro-environmental context of antigenic encounter, and the nature of the Ag itself proposed as key determinants in establishing this balance of signaling [9,10].…”

“…The functional diversity of DC has more recently been explained by the integration of multiple factors within a particular anatomical location causing the differentiation of appropriately tuned ''effector'' DC [9,10]. Although key co-inhibitory receptors, such as ILT3/4, PIR-B, PD-L1 and ICOSL, and immunoregulatory molecules, such as IDO and histone deacetylase HDAC11, have been variously implicated in driving tolerance [11][12][13][14][15][16], it is still not clear to what degree such molecules are universal players.A concern using immature DC in vivo is that they might become activated, particularly within the context of inflammation. If DC are to be used therapeutically, then the tolerant phenotype must be robust and stable.…”