Human type 1 & type 2 conventional dendritic cells express indoleamine 2,3‐dioxygenase 1 with functional effects on T cell priming, 2021, Sittig et al

[Andy]

Dendritic cells (DCs) are key regulators of the immune system that shape T cell responses. Regulation of T cell induction by DCs may occur via the intracellular enzyme indoleamine 2,3‐dioxygenase 1 (IDO), which catalyzes conversion of the essential amino acid tryptophan into kynurenine. Here, we examined the role of IDO in human peripheral blood plasmacytoid DCs (pDCs), and type 1 and type 2 conventional DCs (cDC1s and cDC2s). Our data demonstrates that under homeostatic conditions, IDO is selectively expressed by cDC1s. IFN‐γ or TLR ligation further increases IDO expression in cDC1s and induces modest expression of the enzyme in cDC2s, but not pDCs. IDO expressed by conventional DCs is functionally active as measured by kynurenine production. Furthermore, IDO activity in TLR‐stimulated cDC1s and cDC2s inhibits T cell proliferation in settings were DC‐T cell cell‐cell contact does not play a role. Selective inhibition of IDO1 with epacadostat, an inhibitor currently tested in clinical trials, rescued T cell proliferation without affecting DC maturation status or their ability to cross‐present soluble antigen. Our findings provide new insights into the functional specialization of human blood DC subsets and suggest a possible synergistic enhancement of therapeutic efficacy by combining DC‐based cancer vaccines with IDO inhibition.

Paywall, https://onlinelibrary.wiley.com/doi/10.1002/eji.202048580

 

[Jaybee00]

Relevance to the MECFS metabolic trap theory?

 

[FMMM1]

Yip interesting to know if this is relevant to ME or could be.

@Jonathan Edwards post re immune dysregulation(?) here, came to mind:
https://www.s4me.info/threads/me-cf...maintains-status-quo.12949/page-2#post-228586

Neil McGregor gave a talk, at an OMF Community Symposium, in August 2017. Interestingly(?) he identified a snip, in a small genetic study, on the CD207 gene - "The CD207 gene codes for Langerin, which is a protein found in dendritic cells."*

Whether dendritic cells could give rise to immune dysregulation i.e. something like ME I don't know.

From memory the metabolic trap has been replicated in two cell types; whether anyone's [Ron Davis/Robert Phair] trying to replicate it in dendritic cells I don't know.

*https://totoneimbehl.wordpress.com/2018/03/03/neil-mcgregor-omf-standford-19aug2017/

@Snow Leopard interested to know your views re this publication

@Simon M

 

[Snow Leopard]

Whether dendritic cells could give rise to immune dysregulation i.e. something like ME I don't know.

The study suggests that IDO1 inhibition in dendritic cells leads to increased T cell proliferation, in cases where there is no direct cell-cell contact. In the context of the study, this is portrayed as a positive phenomena, which is contrary to Phair's hypothesis. They also observed no change in dendritic cell function (DC maturation status or their ability to cross‐present soluble antigen) when inhibiting IDO1.

The question isn't so much whether a IDO related metabolic trap is possible (many such traps are possible), but whether it has any relevance to disease. (evidence, which so far is lacking).

 

[FMMM1]

The study suggests that IDO1 inhibition in dendritic cells leads to increased T cell proliferation, in cases where there is no direct cell-cell contact. In the context of the study, this is portrayed as a positive phenomena, which is contrary to Phair's hypothesis. They also observed no change in dendritic cell function (DC maturation status or their ability to cross‐present soluble antigen) when inhibiting IDO1.

The question isn't so much whether a IDO related metabolic trap is possible (many such traps are possible), but whether it has any relevance to disease. (evidence, which so far is lacking).

Thank you very much for your insight @Snow Leopard.

 

[FMMM1]

Dendritic cells (DCs) are key regulators of the immune system that shape T cell responses. Regulation of T cell induction by DCs may occur via the intracellular enzyme indoleamine 2,3‐dioxygenase 1 (IDO), which catalyzes conversion of the essential amino acid tryptophan into kynurenine. Here, we examined the role of IDO in human peripheral blood plasmacytoid DCs (pDCs), and type 1 and type 2 conventional DCs (cDC1s and cDC2s). Our data demonstrates that under homeostatic conditions, IDO is selectively expressed by cDC1s. IFN‐γ or TLR ligation further increases IDO expression in cDC1s and induces modest expression of the enzyme in cDC2s, but not pDCs. IDO expressed by conventional DCs is functionally active as measured by kynurenine production. Furthermore, IDO activity in TLR‐stimulated cDC1s and cDC2s inhibits T cell proliferation in settings were DC‐T cell cell‐cell contact does not play a role. Selective inhibition of IDO1 with epacadostat, an inhibitor currently tested in clinical trials, rescued T cell proliferation without affecting DC maturation status or their ability to cross‐present soluble antigen. Our findings provide new insights into the functional specialization of human blood DC subsets and suggest a possible synergistic enhancement of therapeutic efficacy by combining DC‐based cancer vaccines with IDO inhibition.

Paywall, https://onlinelibrary.wiley.com/doi/10.1002/eji.202048580

Re "IDO inhibition", from memory Robert Phair* mentioned that there was a trial of a drug which inhibited IDO1 i.e. in people who were terminally ill with cancer. The patients refused to continue the treatment because of the fatigue it caused.

*One of the OMF Community Symposiums I suppose.