|C01|

Project Area C
Title

Exploitation of negative regulators of TCR signaling for therapeutic lymphocyte engineerin

Research Area

204-05 / Immunology

Project Summary

To tune the activity of engineered T cells requires a detailed understanding of the signaling pathways that positively and negatively control T cell activation. PD-1 is a checkpoint receptor that can downmodulate antigen-induced T cell activation. Using unbiased screens, we have recently identified candidate factors that potentially cooperate with PD-1 or operate in related pathways.

Here we want to explore the role of such molecules in antigen-induced T cell activation and explore their usability as targets for the T cell engineering to improve their function or maintenance. To this end, we will first biochemically investigate the function of candidate PD-1 regulators in T cells in vitro. In addition, we will generate engineered TCR transgenic or CAR transgenic T cells with alterations in putative PD-1 regulators to investigate their role in adoptive lymphocyte transfer models of chronic infection or cancer.
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Project-Related Publications

1. Ferch, U., zum Buschenfelde, C.M., Gewies, A., Wegener, E., Rauser, S., Peschel, C., Krappmann, D., and Ruland, J. (2007). MALT1 directs B cell receptor-induced canonical nuclear factor-kappaB signaling selectively to the c-Rel subunit. Nat Immunol 8, 984-991.
2. Gross, O., Gewies, A., Finger, K., Schafer, M., Sparwasser, T., Peschel, C., Forster, I., and Ruland, J. (2006). Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442, 651-656.
3. Gross, O., Poeck, H., Bscheider, M., Dostert, C., Hannesschläger, N., Endres, S., Hartmann, G., Tardivel, A., Schweighoffer, E., Tybulewicz, V., Mocsai, A., Tschopp, J., and Ruland, J. (2009) Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459, 433-436.
4. Knies, N., Alankus, B., Weilemann, A., Tzankov, A., Brunner, K., Ruff, T., Kremer, M., Keller, U.B., Lenz, G., and Ruland, J. (2015). Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-kappaB and JNK activation. Proc Natl Acad Sci U S A 112, E7230-7238.
5. Neumann, K., Castineiras-Vilarino, M., Hockendorf, U., Hannesschlager, N., Lemeer, S., Kupka, D., Meyer- mann, S., Lech, M., Anders, H.J., Kuster, B., Busch, D.H., Gewies, A., Naumann, R., Groß, O. and Ruland,
J. (2014). Clec12a is an inhibitory receptor for uric acid crystals that regulates inflammation in response to cell death. Immunity 40, 389-399.
6. Pechloff, K., Holch, J., Ferch, U., Schweneker, M., Brunner, K., Kremer, M., Sparwasser, T., Quintanilla- Martinez, L., Zimber-Strobl, U., Streubel, B., Gewies, A., Peschel, C., and Ruland, J. (2010) The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma. J Exp Med 207, 1031-1044.
7. Ruland, J., Duncan, G.S., Elia, A., del Barco Barrantes, I., Nguyen, L., Plyte, S., Millar, D.G., Bouchard, D., Wakeham, A., Ohashi, P.S., et al. (2001). Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappaB and neural tube closure. Cell 104, 33-
8. Ruland, J., and Hartjes, L. (2019). CARD-BCL-10-MALT1 signalling in protective and pathological immunity. Nat Rev Immunol 19, 118-134.
9. Wartewig, T., Kurgyis, Z., Keppler, S., Pechloff, K., Hameister, E., Ollinger, R., Maresch, R., Buch, T., Steiger, K., Winter, C., Rad, R., and Ruland, J. (2017). PD-1 is a haploinsufficient suppressor of T cell lymphomagen- esis. Nature 552, 121-125.
10. Wartewig, T., and Ruland, J. (2019). PD-1 Tumor Suppressor Signaling in T Cell Lymphomas. Trends Immunol 40, 403-414.

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