Toll-like receptor 2–dependent induction of vitamin A–metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity

Santhakumar M. et al. Nature Medicine 15: 401-409 (2009)

Student: Tsan-Tzu Yang (楊璨滋)                   Time: 15:00~16:00, Nov. 25, 2009

Commentator: Dr. Pin Ling (凌斌 博士)           Place: Room 601

Abstract:

     Dendritic cells (DCs), a kind of antigen presenting cells for CD4⁺ T cell activation, have pattern recognition receptors (PRRs) to identify different pathogens. The coordination by PRR such as Toll-like receptors (TLRs) in facilitating DCs activation is unclear. Retinoic acid (RA) is currently demonstrated be a potent inducer for differentiation of regulatory T cells (Treg) in the intestine.^1,2 In this study, the authors found that DCs promoted Treg differentiation and inhibited autoimmunity through TLR-2-dependent production of vitamin A metabolic enzyme. Yeast cell wall-derived zymosan induced signaling pathway via binding to TLR-2 and dectin-1 in splenic DCs following retinal dehydrogenase type 2 (Raldh2) recruitment in vitro and in vivo. Raldh2 is a member of aldehyde dehydrogenase 1 and is a retinol metabolic enzyme to produce RA. Zymosan induced production of interleukin-10 (IL-10) and Foxp3 via RA, which caused anti-inflammation and Treg development. Utilizing RA receptor (RAR nuclear factor) inhibitor or neutralizing antibody against IL-10 and its receptor, the results indicated that Raldh2 and IL-10 do not directly regulate each other, and Raldh2 induced production of RA to activate RAR which regulated transcription of suppressor of cytokine signaling 3 (SOCS3) in the nucleus. SOCS3 as well as IL-10 inhibited p38 MAPK pathway, which regulated production of pro-inflammatory cytokine. In the mice model of experimental autoimmune encephalomyelitis (EAE), zymosan treatment also caused TLR-2-dependent induction of RA and resulted in anti-inflammation, Treg differentiation and autoimmune inhibition. Taken together, the authors demonstrate that zymosan-induced RA plays a role in anti-inflammation and Treg differentiation which downregulates immune responses and protects host from autoimmune EAE.

References:

1.      Makoto Iwata. 2009. Retinoic acid production by intestinal dendritic cells and its role in T-cell trafficking. Seminars in Immunology. 21: 8-13.

2.      Coombes, J.L. et al. 2007. A functionally specialized population of mucosal CD103⁺ DCs induces Foxp3⁺ regulatory T cells via a TGF-b and retinoic acid-dependent mechanism. The Journal of Experimental Medicine. 204: 1757-64.