Development and function of the innate immune system.
The Diefenbach laboratory studies development and function of the innate immune system. Their current and future research is focused on a molecular understanding of how the innate immune system promotes tissue homeostasis by contributing to the adaptation of multicellular organisms to pernicious environments, such as those at barrier surfaces (e.g., intestine, skin).
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Transcriptional control of ILC development and function
Our lab has recently contributed to the discovery of innate lymphoid cells (ILCs), a group of tissue-resident innate lymphocytes located at border surfaces that release cytokines specifically acting on epithelial cells thereby contributing to tissue homeostasis and to the adaptation of the host in response to noxious compounds and tissue damage. A focus has been the analysis of transcriptional programs controlling lineage specification, commitment and function of ILCs. We recently identified a common, Id2-expressing progenitor to all interleukin 7 receptor-expressing, ‘helper-like’ ILC lineages, the CHILP. Interestingly, the CHILP differentiated into ILC2 and ILC3 lineages but not into conventional natural killer (cNK) cells. Instead, the CHILP gave rise to a peculiar NKp46+ IL-7R+ ILC lineage that required T-bet for specification and was distinct of cNK cells or other ILC lineages, the enigmatic ILC1. Previous work of the group has revealed that functional perturbations of ILC predispose to intestinal infections and to chronic inflammatory bowel diseases. It is likely, that such studies will expose primordial functions of the immune system and will identify new targets for the treatment of debilitating chronic inflammatory disorders.
Hernandez, P., T.Mahlakoiv, I.Yang, V.Schwierzeck, N.Nguyen, F.Guendel, K.Gronke, B.Ryffel, C.Hoelscher, L.Dumoutier, J.C. Renauld, S.Suerbaum, P.Staeheli, A.Diefenbach. 2015. Interferon- and interleukin-22 cooperate for the induction of interferon-stimulated genes and control of rotavirus infection. Nature Immunology. 16:698-707.
Klose, C.S.N., M.Flach, L.Möhle, L.Rogell, T.Hoyler, C.Fabiunke, K.Ebert, D.Pfeifer, V.Sexl, D.Fonseca Pereira, R.G.Domingues, H.Veiga-Fernandes, S.Arnold, I.R.Dunay, Y.Tanriver, and A.Diefenbach. 2014. Differentiation of type 1 ILCs from a common progenitor to helper-like innate lymhoid cell lineages. Cell. 157:340-356.
Diefenbach, A., Colonna, M., and Koyasu, S. 2014. Development, differentiation and diversity of innate lymphoid cells. Immunity. 41:354-365.
Klose, C.S.N., E.A.Kiss, V.Schwierzeck, K.Ebert, T.Hoyler, Y.d’Hargues, N.Göppert, A.L.Croxford, A.Waisman, Y.Tanriver, and A.Diefenbach. 2013. A T-bet gradient controls the fate and function of CCR6- RORt+ innate lymphoid cells. Nature. 494:261-265.
Hoyler, T., C.S.N.Klose, A.Souabni, A.Turqueti-Neves, D.Pfeifer, E.L.Rawlins, D.Voehringer, M.Busslinger, and A.Diefenbach. 2012. The transcription factor Gata3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity. 37:634-648.
Vonarbourg, C., A.Mortha, V.L.Bui, P.Hernandez, E.A.Kiss, T.Hoyler, M.Flach, B.Bengsch, R.Thimme, C.Hölscher, M.Hönig, U.Pannicke, K.Schwarz, C.F.Ware, D.Finke, and A.Diefenbach. 2010. Regulated expression of nuclear receptor RORt confers distinct functional fates to NK cell receptor-expressing RORt+ innate lymphocytes. Immunity. 33:736-751.
Sanos, S.L., V.L.Bui, A.Mortha, K.Oberle, C.Heners, C.Johner, and A.Diefenbach. 2009. RORt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nature Immunology. 10:83-91.