Cutting Edge: Induced Indoleamine 2,3 Dioxygenase Expression in Dendritic Cell Subsets Suppresses T Cell Clonal Expansion

Abstract

In mice, immunoregulatory APCs express the dendritic cell (DC) marker CD11c, and one or more distinctive markers (CD8α, B220, DX5). In this study, we show that expression of the tryptophan-degrading enzyme indoleamine 2,3 dioxygenase (IDO) is selectively induced in specific splenic DC subsets when mice were exposed to the synthetic immunomodulatory reagent CTLA4-Ig. CTLA4-Ig did not induce IDO expression in macrophages or lymphoid cells. Induction of IDO completely blocked clonal expansion of T cells from TCR transgenic mice following adoptive transfer, whereas CTLA4-Ig treatment did not block T cell clonal expansion in IDO-deficient recipients. Thus, IDO expression is an inducible feature of specific subsets of DCs, and provides a potential mechanistic explanation for their T cell regulatory properties.

TGFβ1 and Treg cells: alliance for tolerance

“…Because T reg cells induce TGFβ1 in APCs, it is possible that there is signaling cross-talk in DCs that leads to TGFβ1 production. CTLA-4-Ig treatment causes Tcell anergy, which is dependent on IDO expression, because IDO-deficient DCs are not capable of inducing T-cell tolerance [80]. However, it is unclear whether TGFβ1 production is also impaired in IDO-deficient DCs.…”

Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase

“…This occurs via binding of cell surface CTLA4 on Tregs to B7.1/B7.2 molecules on DCs, resulting in B7-mediated induction of IDO (10,28). Consistent with this, we found that the addition of Tregs to cocultures of TDLN pDCs plus OT-I significantly increased IDO enzymatic activity (measured as production of kynurenine, the first major metabolite of tryptophan produced by IDO) and that this Treg-induced enhancement was prevented by blocking CTLA4 in cocultures (Supplemental Figure 5).…”

“…Even a small minority of IDO + DCs is capable of inhibiting all T cell responses in culture, including dominant inhibition of T cells responding to antigens presented by other nonsuppressive APCs (1). In vivo, pharmacologic activation of the IDO pathway systemically can completely inhibit clonal expansion of large numbers of alloreactive T cells (10). However, the number of IDO + DCs in that become activated in spleen or TDLNs is tiny (less than 1% of total cells, and typically less than 25% of total DCs), and it is unclear how the effects of IDO could create such potent and dominant immunosuppression.…”

Mesenchymal stromal cells: more than inhibitory cells

“…14 In 2004, a paper by Meisel et al 15 showed that one of the mechanisms involved in immune modulatory effect of MSCs is based on the activity of indoleamine 2,3-dioxygenase, whose role in the regulation of dendritic cell functions was already clear. 16,17 Other groups confirmed these data using different immune effector cells. 18,19 In this Leukemia issue, Meisel et al go further showing that human MSCs, once primed with inflammatory cytokines, have anti-microbial effector functions against different pathogens, including bacteria, protozoal parasites and viruses, and that indoleamine 2,3-dioxygenase has a role in the underlying molecular mechanisms.…”