The analysis of mouse models in order to define the roles of IKK/NF-KappaB and JNK signaling in lymphocyte physiology and pathology
Zusammenfassung der Projektergebnisse
Our immune system protects us against dangerous invading micro-organisms. Upon recognition of foreign pathogenic particles specialized signaling pathways are activated within immune cells, which ultimately cause reprogramming of gene expression. Often immune cells are then expanded to effectively combat the invaders. However, immune cells can also cause pathology: exaggerated responses can cause allergies, failure to distinguish between foreign and self can lead to autoimmunity, whereas uncontrolled expansion can result in leukemias and lymphomas. The NF-κB and c-Jun N-terminal Kinase (JNK) signaling pathways are critical for proper immune cell function and their deregulation has frequently been observed in human immunopathology. We therefore investigated genetically modified mice to study how misguided NF-κB and JNK signaling can contribute to autoimmunity and malignancy. We demonstrated that constitutive canonical NF-κB activation in mouse B cells sporadically leads to lymphomas. These are characterized by additional oncogenic alterations such as loss of the tumor suppressor locus INK4a/ARF and other loci, which were not yet associated with lymphomas, amongst them Rc3h1. NF-κB activation strongly collaborates with other relevant oncogenic events, such as loss of Blimp-1 or overexpression of Tcl1. In contrast, we did not observe major pathogenic effects of constitutive JNK activation in mouse B cells, indicating that constitutive JNK signaling alone is not a strong driver of immunopathology in these cells. We then set out to characterize the consequences of loss of Rc3h1, identified in our model lymphomas, in the mouse. Knockout of Roquin1/Rc3h1 is perinatally lethal in mice, which display spinal cord and lung abnormalities. Ablation of Roquin1 in B cells causes hyper-reactivity, but also differentiation defects. In T cells Roquin1, together with its paralog Roquin2, prevents spontaneous follicular helper T cell differentiation. Roquin1/2 function by destabilizing mRNAs of critical immune genes. In further studies we defined the role of the peculiar semi-invariant NKT cell TCR, upstream of NF-κB and JNK signals, for mature NKT cell identity and function. We discovered that, while this receptor can continuously recognize (self-) antigens, surprisingly it is dispensable for mature NKT cell survival and innate functions. Finally, by removing the NF-κB negative regulator A20, we established the first mouse model for hyper-inflammatory mast cells. We showed that these exacerbate experimental induction of arthritis and innate forms of asthma in mice, suggesting that innate activation of mast cells could contribute to these disease entities.
Projektbezogene Publikationen (Auswahl)
- (2008). NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF:BAFF-R-mediated survival signals in B cells. Proc Natl Acad Sci USA 105, 10883–10888
Sasaki, Y., Calado, D.P., Derudder, E., Zhang, B., Shimizu, Y., Mackay, F., Nishikawa, S.-I., Rajewsky, K., and Schmidt-Supprian, M.
- (2009). Development of immunoglobulin lambda-chain-positive B cells, but not editing of immunoglobulin kappa-chain, depends on NF-kappaB signals. Nat Immunol 10, 647–654
Derudder, E., Cadera, E.J., Vahl, J.C., Wang, J., Fox, C.J., Zha, S., van Loo, G., Pasparakis, M., Schlissel, M.S., Schmidt-Supprian, M. and Klaus Rajewsky
- (2011). "Loss of Roquin induces early death and immune deregulation but not autoimmunity." J Exp Med 208(9): 1749-56
Bertossi, A., Aichinger, M., Sansonetti, P., Lech, M., Neff, F., Pal, M., Wunderlich, F. T., Anders, H. J., Klein, L. and Schmidt-Supprian, M.
- (2011). B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood 117, 2227–2236
Chu, Y., Vahl, J.C., Kumar, D., Heger, K., Bertossi, A., Wójtowicz, E., Soberon, V., Schenten, D., Mack, B., Reutelshöfer, M., Beyaert R., Amann, K., van Loo, G. and Marc Schmidt-Supprian
- (2012). A20 and CYLD Do Not Share Significant Overlapping Functions during B Cell Development and Activation. J Immunol 189, 4437–4443
Chu, Y., Soberon, V., Glockner, L., Beyaert, R., Massoumi, R., van Loo, G., Krappmann, D., and Schmidt-Supprian, M.
(Siehe online unter https://doi.org/10.4049/jimmunol.1200396) - (2013): “Combined loss of Roquin paralogs 1 and 2 derepresses Icos and Ox40 target mRNAs and imposes Tfh differentiation on CD4 (+) T cells”; Immunity 38(4):655-68 (22.1)
Vogel, U.K., Edelmann, S.L., Jeltsch, K.M., Bertossi, A., Heger, K., Heinz, G.A., Zöller, J., Warth, S. C., Hoefig, K.P., Lohs, C., Neff, F., Kremmer, E., Schick, J., Repsilber, D., Geerlof, A., Blum, H., Wurst, W., Heikenwälder, M., Schmidt-Supprian, M. and Heissmeyer, V.
- (2013): “NKT Cell-TCR Expression Activates Conventional T Cells in Vivo, But Is Largely Dispensable for Mature NKT Cell Biology”; PLOS Biology, 6(11): e1001589
Vahl, J.C., Heger, K., Knies, N., Hein, M.Y., Boon, L., Yagita, H., Polic, B. and Schmidt-Supprian, M.
(Siehe online unter https://doi.org/10.1371/journal.pbio.1001589) - (2014). “CreERT2 expression from within the c-Kit gene locus allows efficient inducible gene targeting in and ablation of mast cells”; Eur J Immunol. Jan;44(1):296-306
Heger, K., Seidler, B.J. Vahl, J.C., Schwartz, C., Kober, M., Klein, S., Voehringer, D., Saur, D. and Schmidt-Supprian, M.
(Siehe online unter https://doi.org/10.1002/eji.201343731) - (2014): „A20-Deficient Mast Cells Exacerbate Inflammatory Responses In Vivo“. PLOS Biology; 12(1): e1001762
Heger K., Fierens K., Vahl J.C., Aszodi A., Peschke K., Schenten D., Hammad H., Beyaert R., Saur D., van Loo G., Roers A., Lambrecht B.N., Kool M. and Schmidt- Supprian M.
(Siehe online unter https://doi.org/10.1371/journal.pbio.1001762)
