Eat, drink, breathe T cells

T cells constitute a pivotal component of our adaptive immune system, playing a dominant role in the immune response against viruses and cancer. The metabolic programs governing T cell function are of exceptional significance, dictating their behaviors and determining functional outcomes. Thus, unraveling the intricacies of T cell metabolic adaptations in specific contexts assumes critical importance. Such insights are integral to comprehending the mechanisms underlying immune defense against pathogens and malignancies, all while preserving tissue homeostasis.

Our research endeavors are centered around three fundamental domains:

1. Deciphering T Cell Metabolic Demands: We strive to elucidate the precise metabolic requisites that govern T cell functionality. This involves unraveling the intricate network of metabolic pathways that fuel these cells under diverse conditions.
2. Metabolic Pathways and T Cell Differentiation/Function: We are dedicated to investigating the profound impact of metabolic pathways on the differentiation and functional attributes of T cells. This pursuit involves unraveling the interplay between metabolic cues and T cell fate decisions.
3. Translating Insights into Innovative Medical Technologies: We are committed to harnessing the knowledge gleaned from our investigations to catalyze the development of novel medical technologies. Our aim is to exploit these findings for the advancement of therapeutic interventions.

In recent years, our research activities have yielded substantial breakthroughs across these domains. We have unveiled the critical role of processes such as mitochondrial biogenesis and water metabolism in governing the functionality of T cells. Additionally, we have probed into the responses of T cells in the context of metabolic disorders, revealing compromised immune responses in affected individuals. Notably, we have pioneered an innovative technology designed to augment the efficacy of adoptive T cell transfer therapy, particularly in the treatment of solid tumors.

Collectively, our research thrusts not only enhance our fundamental understanding of T cell metabolism but also hold the promise of translating these insights into tangible advancements in medical science. This could ultimately revolutionize therapeutic approaches and bolster our arsenal against challenging diseases.

• Elucidate key molecular processes maintaining quiescence in T cells.
• Metabolic networks in T cells: role of mitochondria in maturation and function of T cells
• Immune memory: The role of mitochondrial membrane potential in fate decision of naïve CD8⁺ T cells
• Cancer research: Targeting T-lymphocyte quiescence as a novel treatment for T-ALL (T-cell acute lymphoblastic leukemia) and other T-cell-malignancies.​

1. Malka Y., Steiman-Shimony A., Rosenthal E., Argaman L., Cohen-Daniel L., Arbib E., Margalit H., Kaplan T*., and Berger, M*. (2017) Post-transcriptional 3’UTR cleavage of mRNA transcripts generates thousands of stable uncapped autonomous RNA fragments. Nature Communications 8, 2029, doi: 10.1038/s41467-017-02099-7. (Equal contribution with Kaplan T)
2. Sun L, Jiang Z, Acosta-Rodriguez VA, Berger M, Du X, Choi JH et al. (2017) HCFC2 is needed for IRF1- and IRF2-dependent Tlr3 transcription and for survival during viral infections. The Journal of Experimental Medicine 214, 3263-3277.
3. Omar, I., Rom, O., Aviram, M., Cohen-Daniel, L., Gebre, AK., Parks, JS., and Berger, M. (2017) Slfn2 mutation-induced loss of T cell quiescence leads to elevated de novo sterol synthesis. Immunology 152, 484-493.
4. Molho-Pessach, V., Ramot, Y., Mogilevsky, M., Cohen-Daniel, L., Eisenstein, E. M., Abu-Libdeh, A., Siam, I.,Berger, M., Karni, R., and Zlotogorski, A. (2017) Generalized verrucosis and abnormal T cell activation due to homozygous TAOK2 mutation, J Dermatol Sci.
5. Lapenna, A., Omar, I., and Berger, M. (2017) A novel spontaneous mutation in the TAP2 gene unravels its role in macrophage survival, Immunology 150, 432-443.
6. Wang, Y., Su, L., Morin, M. D., Jones, B. T., Whitby, L. R., Surakattula, M. M., Huang, H^S., Shi, H., Choi, J. H., Wang, K. W., Moresco, E. M., Berger, M., Zhan, X., Zhang, H., Boger, D. L., and Beutler, B. (2016) TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS, Proc Natl Acad Sci U S A 113, E884-893.
7. Omar, I., Lapenna, A., Cohen-Daniel, L., Tirosh, B., and Berger, M. (2016) Schlafen2 mutation unravels a role for chronic ER stress in the loss of T cell quiescence, Oncotarget 7, 39396-39407.
8. Morin, M. D., Wang, Y., Jones, B. T., Su, L., Surakattula, M. M., Berger, M., Huang, H., Beutler, E. K., Zhang, H., Beutler, B., and Boger, D. L. (2016) Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists, J Med Chem.
9. Goldshtein, A., Zerbib, S. M., Omar, I., Cohen-Daniel, L., Popkin, D., and Berger, M. (2016) Loss of T-cell quiescence by targeting Slfn2 prevents the development and progression of T-ALL, Oncotarget 7, 46835- 46847.
10. Finkin, S., Yuan, D., Stein, I., Taniguchi, K., Weber, A., Unger, K., Browning, J. L., Goossens, N., Nakagawa, S., Gunasekaran, G., Schwartz, M. E., Kobayashi, M., Kumada, H., Berger, M., Pappo, O., Rajewsky, K., Hoshida, Y., Karin, M., Heikenwalder, M., Ben-Neriah, Y., and Pikarsky, E. (2015) Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma, Nat Immunol 16, 1235-1244.
11. Benhamron, S., Pattanayak, S. P., Berger, M., and Tirosh, B. (2015) mTOR activation promotes plasma cell differentiation and bypasses XBP-1 for immunoglobulin secretion, Mol Cell Biol 35, 153-166.
12. Goldshtein, A., and Berger, M. (2014) Friend or foe: can activating mutations in NOTCH1 contribute to a favorable treatment outcome in patients with T-ALL?, Crit Rev Oncog 19, 399-404.
13. Sabouri, A. H., Marcondes, M. C. G., Flynn, C., Berger, M., Xiao, N., Fox, H. S., and Sarvetnick, N. E. (2014) TLR signaling controls lethal encephalitis in WNV-infected brain, Brain Res 1574, 84-95.
14. Tardif, V., Manenkova, Y., Berger, M., Hoebe, K., Zuo, J.-P., Yuan, C., Kono, D. H., Theofilopoulos, A. N., and Lawson, B. R. (2013) Critical role of transmethylation in TLR signaling and systemic lupus erythematosus, Clin Immunol147, 133-143.
15. Arnold, C. N., Barnes, M. J., Berger, M., Blasius, A. L., Brandl, K., Croker, B., Crozat, K., Du, X., Eidenschenk, C., Georgel, P., Hoebe, K., Huang, H., Jiang, Z., Krebs, P., La Vine, D., Li, X., Lyon, S., Moresco, E. M., Murray, A. R., Popkin, D. L., Rutschmann, S., Siggs, O. M., Smart, N. G., Sun, L., Tabeta, K., Webster, V., Tomisato, W., Won, S., Xia, Y., Xiao, N., and Beutler, B. (2012) ENU-induced phenovariance in mice: inferences from 587 mutations, BMC Res Notes5, 577.
16. Siggs, O. M., Berger, M., Krebs, P., Arnold, C. N., Eidenschenk, C., Huber, C., Pirie, E., Smart, N. G., Khovananth, K., Xia, Y., McInerney, G., Karlsson Hedestam, G. B., Nemazee, D., and Beutler, B. (2010) A mutation of Ikbkg causes immune deficiency without impairing degradation of IkappaB alpha, Proc Natl Acad Sci U S A 107, 3046-3051.
17. Berger, M., Krebs, P., Crozat, K., Li, X., Croker, B. A., Siggs, O. M., Popkin, D., Du, X., Lawson, B. R., Theofilopoulos, A. N., Xia, Y., Khovananth, K., Moresco, E. M., Satoh, T., Takeuchi, O., Akira, S., and Beutler, B. (2010) An Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence, Nat Immunol 11, 335-343.
18. Louria-Hayon, I., Alsheich-Bartok, O., Levav-Cohen, Y., Silberman, I., Berger, M., Grossman, T., Matentzoglu, K., Jiang, Y. H., Muller, S., Scheffner, M., Haupt, S., and Haupt, Y. (2009) E6AP promotes the degradation of the PML tumor suppressor, Cell Death Differ 16, 1156-1166.
19. Croker, B. A., Lawson, B. R., Rutschmann, S., Berger, M., Eidenschenk, C., Blasius, A. L., Moresco, E. M., Sovath, S., Cengia, L., Shultz, L. D., Theofilopoulos, A. N., Pettersson, S., and Beutler, B. A. (2008) Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger, Proc Natl Acad Sci U S A105, 15028-15033.
20. Croker, B., Crozat, K., Berger, M., Xia, Y., Sovath, S., Schaffer, L., Eleftherianos, I., Imler, J. L., and Beutler, B. (2007) ATP-sensitive potassium channels mediate survival during infection in mammals and insects, Nat Genet 39, 1453-1460.
21. Berger, M., Stahl, N., Del Sal, G., and Haupt, Y. (2005) Mutations in proline 82 of p53 impair its activation by Pin1 and Chk2 in response to DNA damage, Mol Cell Biol 25, 5380-5388.
22. Haupt, S., Berger, M., Goldberg, Z., and Haupt, Y. (2003) Apoptosis – the p53 network, J Cell Sci 116, 4077-4085.
23. Goldberg, Z., Vogt Sionov, R., Berger, M., Zwang, Y., Perets, R., Van Etten, R. A., Oren, M., Taya, Y., and Haupt, Y. (2002) Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation, EMBO J 21, 3715-3727.
24. Sionov, R. V., Coen, S., Goldberg, Z., Berger, M., Bercovich, B., Ben-Neriah, Y., Ciechanover, A., and Haupt, Y. (2001) c-Abl regulates p53 levels under normal and stress conditions by preventing its nuclear export and ubiquitination, Mol Cell Biol 21, 5869-5878.
25. Berger, M., Vogt Sionov, R., Levine, A. J., and Haupt, Y. (2001) A role for the polyproline domain of p53 in its regulation by Mdm2, J Biol Chem 276, 3785-3790.
26. Muller, S., Berger,M., Lehembre, F., Seeler, J. S., Haupt, Y., and Dejean, A. (2000) c-Jun and p53 activity is modulated by SUMO-1 modification, J Biol Chem 275, 13321-13329.
27. Unger, T.,Juven-Gershon, T., Moallem, E., Berger, M., Vogt Sionov, R., Lozano, G., Oren, M., and Haupt, Y. (1999) Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2, EMBO J 18, 1805-1814.
28. Sionov, R. V., Moallem, E., Berger, M., Kazaz, A., Gerlitz, O., Ben-Neriah, Y., Oren, M., and Haupt, Y. (1999) c-Abl neutralizes the inhibitory effect of Mdm2 on p53, J Biol Chem 274, 8371-8374.

Book Chapter

Berger M, Haupt Y. Flow cytometric analysis of p53-induced apoptosis. Methods Mol Biol. 234:245-56 (2003).

• Alwin Kramer, German Cancer Research Center and Dept. of Internal Medicine, University of Heidelberg, Germany. Targeting lymphocytes quiescence as a treatment for T-ALL treatment. Holding a shared grant, German Cancer Research Center (DKFZ)-Israel Ministry of Science & Technology.
• Magdalena Huber, Institute for Medical Microbiology and Hygiene Medicine Marburg University Germany. Role of mitochondrial complex V restriction in responsiveness of naïve CD8 T cells.
• Daniel Popkin, Case Western Reserve University, Cleveland, OH, USA. Role of Slfn2 in T-ALL development. Two joint papers.
• John Parks, Wake Forest School of Medicine, Winston-Salem, NC, USA. Lipid and cholesterol metabolism in T cells. One joint paper.