Self-control by natural killer cells:
the trail between tissue remodeling, tumor surveillance and autoimmunity
Andreas Diefenbach, University of Freiburg, Medical Center

My laboratory studies the development, function and tolerance of natural killer (NK) cells. We are striving to understand the molecular basis of how NK cells recognize tumor cells and virally infected cells. A focus has been the characterization of stimulatory NK cell recognition receptors and their specificities. Our studies have led to the identification of a family of class I MHC-related molecules as ligands for one activating NK cell receptor, NKG2D. We found that these ligands are not expressed by most normal cells but upregulated following various forms of cellular stress (including tumor transformation and infection). An important problem is the question of the molecular programs regulating NKG2D ligand expression. Elucidation of these mechanisms will help us to understand how normal protective immune responses differ from inappropriate ones that result in inflammation and autoimmunity.

Our studies concerning mucosal NK cells have led to the identification of a novel lymphocyte population that co-expresses NK cell receptors and the orphan nuclear receptor RORgt. Interestingly, these cells are distinct from authentic NK cells in that they are related to a lymphocyte population which induces differentiation of secondary lymphoid organs in the fetus (called lymphoid tissue inducer cells, LTic). We are currently investigating the lineage relationship between these NK-like cells and LTic.

We found that the RORgt-expressing NK-like cells differentiate under the influence of the commensal microflora and are an important source of the cytokine IL-22. The IL-22 receptor is exclusively expressed by epithelial cells and IL-22R signalling leads to the upregulation of molecules involved in maintaining epithelial homeostasis. We are currently identifying the molecular targets of IL-22 in epithelial cells. These studies will allow us to identify target genes involved in the protection against inflammatory bowel diseases (ulcerative colitis and Crohn’s disease).

Literature

Sanos, S., V.L.Bui, A.Mortha, K.Oberle, C.Heners, C.Johner and A.Diefenbach. 2009. RORgt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nature Immunology. 10:83-91.

Lucas, M., W.Schachterle, K.Oberle, P.Aichele, and A.Diefenbach. 2007. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity. 26:503-517.

Diefenbach, A., E.Tomasello, M.Lucas, A.M.Jamieson, J.K.Hsia, E.Vivier, and D.H.Raulet. 2002. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nature Immunology. 3:1142-1149.

Diefenbach, A., E.R.Jensen, A.M.Jamieson, and D.H.Raulet. 2001. Rae1 and H60 ligands of the NKG2D receptor stimulate tumor immunity. Nature. 413:165-171.

Diefenbach, A., A.M.Jamieson, S.D.Liu, N.Shastri, and D.H.Raulet. 2000. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nature Immunology. 1:119-126.

Diefenbach, A., H.Schindler, M.Röllinghoff, W.Yokoyama, and C.Bogdan. 1999. Requirement of Type 2 NO Synthase for IL-12 Signaling in Innate Immunity. Science. 284:951-955.

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