Ulrike Lorenz, PhD

Division

• Immunobiology

Additional Titles

• Executive Director of Bursky Center for Human Immunology & Immunotherapy Programs (CHiiPs)

Education

• Diplom, Biochemistry, Freie Universität Berlin
• Ph.D., Max-Planck Institut für Molekulare Genetik, Freie Universität Berlin

Research Statement

A healthy physiological immune system is built on a continuous balance between a productive immune response to pathogens and tolerance to self. Under patho-physiological conditions, such as loss of tolerance to self, autoimmune diseases develop. On the other hand, tolerance to tumors and the lack of an effective immune response is a hurdle that needs to be overcome in cancer immunotherapy. For T cells, immune tolerance is achieved and maintained in two ways; central and peripheral tolerance. Central tolerance is completed during thymic T cell development when potentially auto-reactive T cells undergo cell death. Peripheral tolerance occurs at many levels, one of which is mediated by a specialized subtype of T cells, the so-called regulatory T cells (Tregs), which have been shown to suppress the immune response and thereby control potentially harmful responses to self. It is now widely accepted that dysregulated Treg cell-mediated suppression is a major contributor of autoimmune diseases, and that the induction/activation of Treg cells can promote tumor tolerance both naturally and during anti-tumor immune therapy. Our lab has a long-standing interest in the role of the protein tyrosine phosphatase SHP-1 in T cell activation, development, and function. Over the last years, our focus has shifted to the role of SHP-1 in regulating the balance between T cell activation and suppression. We have recently generated several new mouse models to specifically interfere with SHP-1 activity in T cell subsets. Using these models, we identified a novel, previously unappreciated mechanism of SHP-1 influencing immune tolerance by affecting the susceptibility of conventional T cells to regulatory T cell-mediated suppression. We are currently working on how SHP-1 modulates downstream signaling molecules and thereby controls the susceptibility to suppression as well as how SHP-1 modulates the activity of Treg cells. These projects have implications for the prevention/treatment of autoimmune diseases as well as boosting tumor immunity. Complementing our genetic approaches, we have recently developed a novel protein degron system that allows for fast, but reversible highly specific protein depletion in vitro and in vivo. We are currently using this approach to improve the safety of chimeric antigen receptor (CAR) T cells. While the recent CAR T cell therapies have shown impressive efficacy, the amount of associated severe morbidities is significant. Improving the safety is therefore of great clinical interest.

Selected Publications

Medina CB, Chiu YH, Stremska ME, Lucas CD, Poon I, Tung KS, Elliott MR, Desai B, Lorenz UM, Bayliss DA, Ravichandran KS. Pannexin 1 channels facilitate communication between T cells to restrict the severity of airway inflammation. Immunity. 2021 Aug 10;54(8):1715-1727.e7. doi: 10.1016/j.immuni.2021.06.014. Epub 2021 Jul 21. PubMed PMID: 34283971; PubMed Central PMCID: PMC8363584.

Chiu YH, Medina CB, Doyle CA, Zhou M, Narahari AK, Sandilos JK, Gonye EC, Gao HY, Guo SY, Parlak M, Lorenz UM, Conrads TP, Desai BN, Ravichandran KS, Bayliss DA. Deacetylation as a receptor-regulated direct activation switch for pannexin channels. Nat Commun. 2021 Jul 23;12(1):4482. doi: 10.1038/s41467-021-24825-y. PubMed PMID: 34301959; PubMed Central PMCID: PMC8302610.

Senthivinayagam S, Serbulea V, Upchurch CM, Polanowska-Grabowska R, Mendu SK, Sahu S, Jayaguru P, Aylor KW, Chordia MD, Steinberg L, Oberholtzer N, Uchiyama S, Inada N, Lorenz UM, Harris TE, Keller SR, Meher AK, Kadl A, Desai BN, Kundu BK, Leitinger N. Adaptive thermogenesis in brown adipose tissue involves activation of pannexin-1 channels. Mol Metab. 2021 Feb;44:101130. doi: 10.1016/j.molmet.2020.101130. Epub 2020 Nov 25. PubMed PMID: 33248294; PubMed Central PMCID: PMC7779784.

Medina CB, Mehrotra P, Arandjelovic S, Perry JSA, Guo Y, Morioka S, Barron B, Walk SF, Ghesquière B, Krupnick AS, Lorenz UM, Ravichandran KS. Metabolites released from apoptotic cells act as tissue messengers. Nature. 2020 Apr;580(7801):130-135. doi: 10.1038/s41586-020-2121-3. Epub 2020 Mar 18. PubMed PMID: 32238926; PubMed Central PMCID: PMC7217709.

Shi L, Li K, Guo Y, Banerjee A, Wang Q, Lorenz UM, Parlak M, Sullivan LC, Onyema OO, Arefanian S, Stelow EB, Brautigan DL, Bullock TNJ, Brown MG, Krupnick AS. Modulation of NKG2D, NKp46, and Ly49C/I facilitates natural killer cell-mediated control of lung cancer. Proc Natl Acad Sci U S A. 2018 Nov 13;115(46):11808-11813. doi: 10.1073/pnas.1804931115. Epub 2018 Oct 31. PubMed PMID: 30381460; PubMed Central PMCID: PMC6243255.

Sharma AK, Charles EJ, Zhao Y, Narahari AK, Baderdinni PK, Good ME, Lorenz UM, Kron IL, Bayliss DA, Ravichandran KS, Isakson BE, Laubach VE. Pannexin-1 channels on endothelial cells mediate vascular inflammation during lung ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol. 2018 Aug 1;315(2):L301-L312. doi: 10.1152/ajplung.00004.2018. Epub 2018 May 10. PubMed PMID: 29745255; PubMed Central PMCID: PMC6139659.

Jankowski J, Perry HM, Medina CB, Huang L, Yao J, Bajwa A, Lorenz UM, Rosin DL, Ravichandran KS, Isakson BE, Okusa MD. Epithelial and Endothelial Pannexin1 Channels Mediate AKI. J Am Soc Nephrol. 2018 Jul;29(7):1887-1899. doi: 10.1681/ASN.2017121306. Epub 2018 Jun 4. PubMed PMID: 29866797; PubMed Central PMCID: PMC6050932.

Good ME, Chiu YH, Poon IKH, Medina CB, Butcher JT, Mendu SK, DeLalio LJ, Lohman AW, Leitinger N, Barrett E, Lorenz UM, Desai BN, Jaffe IZ, Bayliss DA, Isakson BE, Ravichandran KS. Pannexin 1 Channels as an Unexpected New Target of the Anti-Hypertensive Drug Spironolactone. Circ Res. 2018 Feb 16;122(4):606-615. doi: 10.1161/CIRCRESAHA.117.312380. Epub 2017 Dec 13. PubMed PMID: 29237722; PubMed Central PMCID: PMC5815904.

Mercadante ER, Lorenz UM. T Cells Deficient in the Tyrosine Phosphatase SHP-1 Resist Suppression by Regulatory T Cells. J Immunol. 2017 Jul 1;199(1):129-137. doi: 10.4049/jimmunol.1602171. Epub 2017 May 26. PubMed PMID: 28550200; PubMed Central PMCID: PMC5510748.

Mercadante ER, Lorenz UM. Breaking Free of Control: How Conventional T Cells Overcome Regulatory T Cell Suppression. Front Immunol. 2016;7:193. doi: 10.3389/fimmu.2016.00193. eCollection 2016. Review. PubMed PMID: 27242798; PubMed Central PMCID: PMC4870238.

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Assistant:
Elizabeth Moore
314-362-9103
melizabeth@wustl.edu