Institute for Molecular and Clinical Immunology, Medical Faculty,
Defining the IL-7 niche for local and systemic ILC homeostasis
Cytokine production by non-hematopoietic stromal cells regulates immune cell development and function, e.g. in the BM and in LNs. IL-7 is a classical stromal cell-derived cytokine and is crucial for T and B cell development. Importantly, it also promotes the development and function of ILCs. IL-7 is produced e.g. in the BM and intestine. However, the relative contribution of different IL-7-producing cell types/organs to the modulation of local and systemic ILC responses is still unclear. In order to address this question, we have established and analyzed several tissue-specific IL-7 knockout mice in the first funding period. So far our analyses were mainly focused on the steady state and acute inflammatory conditions. In the next funding period, we would like to extent our analyses to models of colitis-associated colon cancer (CAC). For this purpose, we aim to complement our studies on local and systemic ILC homeostasis in stroma-specific IL-7 knockout mice with our newly established mouse models lacking individual NKp46+ ILC subsets. With the help of both approaches we aim i) to identify those stromal cell types that define the IL-7 niche for ILC homeostasis and function in vivo and ii) to identify those NKp46+ ILCs, which modulate stromal cell function and IL-7-associated CAC-development.
Bank, U., K. Deiser, D. Finke, G.J. Hämmerling, B. Arnold, and T. Schüler. 2016. Cutting Edge: Innate Lymphoid Cells Suppress Homeostatic T Cell Expansion in Neonatal Mice. J Immunol. 196:3532-3536. doi:10.4049/jimmunol.1501643.
Bank, U., K. Deiser, C. Plaza-Sirvent, L. Osbelt, A. Witte, L. Knop, R. Labrenz, R. Jänsch, F. Richter, A. Biswas, A.C. Zenclussen, E. Vivier, C. Romagnani, A.A. Kühl, I.R. Dunay, T. Strowig, I. Schmitz, and T. Schüler. 2020. c-FLIP is crucial for IL-7/IL-15-dependent NKp46+ ILC development and protection from intestinal inflammation in mice. Nat Commun. 11:1056. doi:10.1038/s41467-020-14782-3.
Deiser, K., D. Stoycheva, U. Bank, T. Blankenstein, and T. Schüler. 2016. Interleukin-7 Modulates Anti-Tumor CD8+ T Cell Responses via Its Action on Host Cells. PLoS One. 11:e0159690. doi:10.1371/journal.pone.0159690.
Knop, L., K. Deiser, U. Bank, A. Witte, J. Mohr, L. Philipsen, H.J. Fehling, A.J. Müller, U. Kalinke, and T. Schüler. 2020. IL-7 derived from lymph node fibroblastic reticular cells is dispensable for naive T cell homeostasis but crucial for central memory T cell survival. Eur J Immunol. 10.1002/eji.201948368.
Patra, A.K., A. Avots, R.P. Zahedi, T. Schüler, A. Sickmann, U. Bommhardt, and E. Serfling. 2013. An alternative NFAT-activation pathway mediated by IL-7 is critical for early thymocyte development. Nat Immunol. 14:127-135. doi:10.1038/ni.2507.
Schüler, T., G.J. Hämmerling, and B. Arnold. 2004. Cutting edge: IL-7-dependent homeostatic proliferation of CD8+ T cells in neonatal mice allows the generation of long-lived natural memory T cells. J Immunol. 172:15-19. doi:10.4049/jimmunol.172.1.15.
Sercan, O., G.J. Hämmerling, B. Arnold, and T. Schüler. 2006. Innate immune cells contribute to the IFN-gamma-dependent regulation of antigen-specific CD8+ T cell homeostasis. J Immunol. 176:735-739. doi:10.4049/jimmunol.176.2.735.
Shalapour, S., K. Deiser, A.A. Kühl, R. Glauben, S.M. Krug, A. Fischer, O. Sercan, S. Chappaz, S. Bereswill, M.M. Heimesaat, C. Loddenkemper, M. Fromm, D. Finke, G.J. Hämmerling, B. Arnold, B. Siegmund, and T. Schüler. 2012. Interleukin-7 links T lymphocyte and intestinal epithelial cell homeostasis. PLoS One. 7:e31939. doi:10.1371/journal.pone.0031939.
Shalapour, S., K. Deiser, O. Sercan, J. Tuckermann, K. Minnich, G. Willimsky, T. Blankenstein, G.J. Hämmerling, B. Arnold, and T. Schüler. 2010. Commensal microflora and interferon-gamma promote steady-state interleukin-7 production in vivo. Eur J Immunol. 40:2391-2400. doi:10.1002/eji.201040441.
Stoycheva, D., K. Deiser, L. Stärck, G. Nishanth, D. Schlüter, W. Uckert, and T. Schüler. 2015. IFN-γ regulates CD8+ memory T cell differentiation and survival in response to weak, but not strong, TCR signals. J Immunol. 194:553-559. doi:10.4049/jimmunol.1402058.