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Title: Migratory CD103+ dendritic cells suppress Helminth-driven Type 2 immunity through constitutive expression of IL-12

Author
item EVERTS, B - Washington University School Of Medicine
item TUSSIWAND, R - Washington University School Of Medicine
item DREESEN, L - Washington University School Of Medicine
item FAIRFAX, K - Washington University School Of Medicine
item HUANG, S - Washington University School Of Medicine
item SMITH, A - Washington University School Of Medicine
item ONEIL, C - Washington University School Of Medicine
item LAM, W - Washington University School Of Medicine
item EDELSON, B - Washington University School Of Medicine
item Urban, Joseph
item MURPHY, K - Washington University School Of Medicine
item PEARCE, E - Washington University School Of Medicine

Submitted to: Journal of Experimental Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/25/2015
Publication Date: 1/11/2016
Citation: Everts, B., Tussiwand, R., Dreesen, L., Fairfax, K.C., Huang, S.C., Smith, A.M., Oneil, C.M., Lam, W.Y., Edelson, B.T., Urban Jr, J.F., Murphy, K.M., Pearce, E.J. 2016. Migratory CD103+ dendritic cells suppress Helminth-driven Type 2 immunity through constitutive expression of IL-12. Journal of Experimental Medicine. 213(1):35-51. doi: 10.1084/jem.20150235..

Interpretive Summary: There is a group of immune related cells called classical dendritic cells or cDCs that are highly specialized at capturing and processing antigen for presentation to other immune cells that play a crucial role in the development of adaptive immune responses during infections and inflammatory diseases. A new feature described in this report is the presence of a gene regulatory factor called Batf3 that modulates the function of certain DC populations. When Batf3 is genetically deleted from DCs the cell produces a lot less of a protein called IL-12 that results in a much stronger protective response to infection with parasitic worms. This has an obvious advantage when there is exposure to a worm infection. However, the response to the infection is also much stronger than normal and results in greater tissue inflammation that can be harmful to the host. This suggests that there is a fine level of control of immune homeostasis related to immune activity that can reduce the intensity of the inflammation to make an appropriate response to infection that does not result in overt disease. Understanding the function of this mechanism and the methods to control the infection and reduce the intensity of inflammation is important to good health. Strategies for control of these reactions through diet will also be investigated.

Technical Abstract: Batf3-dependent CD103+ and CD8alpha+ dendritic cells (DCs) play a central role in the development of type 1 immune responses. However, their role in type 2 immunity remains unclear. We found that Th2 cell responses were enhanced in Batf3-/- mice responding to helminth parasite antigens (Ag). As a result, reactions associated with Th2 responses in helminth-infected mice were exaggerated. Specifically, compared to wild type mice, Batf3-/- mice were resistant to primary infection with Heligmosomoides polygyrus, and developed larger, more fibrotic parasite egg-induced hepatic granulomatous lesions following infection with Schistosoma mansoni. Mechanistically, cell-autonomous production of IL-12, selectively by migratory CD103+ DCs independently from commensal signals was necessary and sufficient to exert suppressive effects on Th2 response development. These findings identify a previously unrecognized role for CD103+ DCs in antagonizing type 2 immune responses. This has significant consequences for the outcome of disease development.