432회 Regulation of CD4 T Helper Subset differentiation by Dendritic Ce…

432회   (2010. 2. 1.)

연사: 이 승 우, La Jolla Institute for Allergy and Immunology

제목:  Regulation of CD4 T Helper Subset Differentiation by Dendritic Cells

Abstract 

TGF- can direct the induction of Foxp3+ Treg and also synergize with IL-6 and IL- 4 to induce distinct Th17 and Th9 effector subsets. In contrast, TGF- has generally been considered suppressive for Th1 differentiation. We now report that nitric oxide (NO), a metabolite of L-arginine, reprograms TGF- signals to support development of Th1 cells in an IL-12-independent manner. Furthermore, IL-6 and NO compete in synergizing with TGF- to determine the balance between Foxp3+ Treg, Th17, and Th1 cells. These data illustrate that TGF- can direct development of many lineages of Th cells, and suggest a new mechanism by which NO production, which is associated with protection against intracellular pathogens, ensures effective maintenance of Th1 immunity.  Tolerance mechanisms at mucosal surfaces are critical for maintaining host integrity. We found that 4-1BB, a member of the TNFR family, plays a crucial role in controlling homeostasis in the mucosal organs and gut-associated lymphoid tissues. 4-1BB- deficient mice developed spontaneous autoimmunity, gut and lung inflammation, and lymphomas, associated with deregulation toward a Th1 phenotype with reduced accumulation of Foxp3+ Treg. Th lineage studies showed that mucosal dendritic cells from 4-1BB-/- mice were impaired in generating adaptive Foxp3+ Treg, due to reduced expression of retinal dehydrogenase and an imbalance in production of IL-12 and nitric oxide favoring Th1 differentiation. Thus, 4-1BB controls mucosal regulatory dendritic cells and promotes immune tolerance.