Mark Jay Shlomchik, M.D., Ph.D.
Campus: The Assembly, 5051 Centre Ave
Pittsburgh, PA 15213
- M.D., University of Pennsylvania Medical School, 1989
- Ph.D., University of Pennsylvania, 1989
- B.A., Harvard College, 1981
- UPMC Endowed and Distinguished Professor, Department of Immunology
Overview: Our lab is interested in systemic autoimmune diseases, long-lived B cell immunity, and in immunopathogenesis more broadly. We also work on T cell immunotherapy for cancer using our newly invented TCXpress TCR cloning and functional testing platform.
Autoimmunity research: We are using genetically modified mouse models to address the roles of specific cell types (e.g. B cells, T cells and DCs) in systemic autoimmunity. Currently we are particularly interested in the identity and function of autoreactive T cells that help autoreactive B cells and that infiltrate target tissues using novel TCR cloning methods. A second major area is investigating the regulatory role of TLR9 and stimulatory role of TLR7 in lupus, and to define how TLRs function in tissue-specific fashion. To this end we have made conditional alleles of both TLR7 and TLR9 on a lupus-prone mouse genetic background and we are dissecting the tissue-specific roles of these receptors. We have also introduced key point mutants and chimeric molecules into the germline of this mouse strain to test hypothesis about function in vivo and in signaling assays in vitro. Finally, we continue to work on the role of B cells in lupus and how best to therapeutically target them. To this end we recently have helped elucidate the identity and pathogenic function of Age-associated B Cells (ABC) in a murine model of lupus.
B cell immunity: we are investigating the mechanisms of cellular selection and differentiation in the germinal center (GC), a site of rapid proliferation, mutation, and differentiation into memory B cells (MBC). We recently showed that the GC shifts its output from MBC to plasma cells as it matures with time. We are actively working on “non-canonical” extrafollicular B cell responses, which induce isotype switch and mutation outside of GC as well as generate MBC; a key question is what controls the choice between these two types of response. We have also identified novel subsets of MBC in mice and are studying their origins and function using epigenetic, single cell, and subpopulation gene expression analysis. Our work on MBC has now been extended to humans, where, by studying multiple lymphoid and mucosal tissues, we have identified novel populations of MBC.
T cell immunotherapy: Our patented TCXpress technology allows for rapid cloning and expression of TCRs from hundreds to thousands at a time using a robotic platform, at which point TCRs can be tested for function. We have applied this to show proof of concept for neoantigen-specific TCR therapy of solid tumors as well as minor histocompatibility-specific T cell therapy for leukemia. This work is supported by a Pitt spinoff company BlueSphere Bio (bluespherebio.com)
Training and mentoring: Dr. Shlomchik is the PI of a T32 on Autoimmunity and Immunopathology. He has trained over 50 students and fellows, most of whom remain in science and several of whom have independent faculty positions. His position as a physician-scientist conducting disease-related basic research has enabled him to provide a combination of scientific and career advice and mentoring that have in turn made his lab an attractive destination for trainees with similar interests and background.
1. Weisel, F.J., G.V. Zuccarino-Catania, M. Chikina, and M.J. Shlomchik. 2016. A Temporal Switch in the Germinal Center Determines Differential Output of Memory B and Plasma Cells. Immunity. 44:116-30.
2. Giles, J.R., A.T. Neves, A. Marshak-Rothstein, and M.J. Shlomchik. 2017. Autoreactive helper T cells alleviate the need for intrinsic TLR signaling in autoreactive B cell activation. JCI Insight. 2:e90870.
3. Luo, W., F. Weisel, and M.J. Shlomchik. 2018. B Cell Receptor and CD40 Signaling Are Rewired for Synergistic Induction of the c-Myc Transcription Factor in Germinal Center B Cells. Immunity. 48:313-26 e5.
4. Tilstra, J.S., L. Avery, A.V. Menk, R.A. Gordon, S. Smita, L.P. Kane, M. Chikina, G.M. Delgoffe, and M.J. Shlomchik. 2018. Kidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhausted. J Clin Invest. 128:4884-97.
5. Elsner, R.A. and M.J. Shlomchik. 2019. IL-12 Blocks Tfh Cell Differentiation during Salmonella Infection, thereby Contributing to Germinal Center Suppression. Cell Rep. 29:2796-809 e5.
6. Luo, W., W. Hawse, L. Conter, N. Trivedi, F. Weisel, D. Wikenheiser, R.T. Cattley, and M.J. Shlomchik. 2019. The AKT kinase signaling network is rewired by PTEN to control proximal BCR signaling in germinal center B cells. Nat Immunol. 20:736-46.
7. Shlomchik, M.J., W. Luo, and F. Weisel. 2019. Linking signaling and selection in the germinal center. Immunological Reviews. 288:49-63.
8. Trivedi, N., F. Weisel, S. Smita, S. Joachim, M. Kader, A. Radhakrishnan, C. Clouser, A.M. Rosenfeld, M. Chikina, F. Vigneault, U. Hershberg, N. Ismail, and M.J. Shlomchik. 2019. Liver Is a Generative Site for the B Cell Response to Ehrlichia muris. Immunity. 51:1088-101 e5.
9. Elsner, R.A. and M.J. Shlomchik. 2020. Germinal Center and Extrafollicular B Cell Responses in Vaccination, Immunity, and Autoimmunity. Immunity. 53:1136-50.
10. Tilstra, J.S., S. John, R.A. Gordon, C. Leibler, M. Kashgarian, S. Bastacky, K.M. Nickerson, and M.J. Shlomchik. 2020. B cell-intrinsic TLR9 expression is protective in murine lupus. J Clin Invest. 130:3172-87.
11. Weisel, F.J., S.J. Mullett, R.A. Elsner, A.V. Menk, N. Trivedi, W. Luo, D. Wikenheiser, W.F. Hawse, M. Chikina, S. Smita, L.J. Conter, S.M. Joachim, S.G. Wendell, M.J. Jurczak, T.H. Winkler, G.M. Delgoffe, and M.J. Shlomchik. 2020. Germinal center B cells selectively oxidize fatty acids for energy while conducting minimal glycolysis. Nat Immunol. 21:331-42.
12. Weisel, N.M., F.J. Weisel, D.L. Farber, L.A. Borghesi, Y. Shen, W. Ma, E.T. Luning Prak, and M.J. Shlomchik. 2020. Comprehensive analyses of B-cell compartments across the human body reveal novel subsets and a gut-resident memory phenotype. Blood. 136:2774-85.
13. Gordon, R.A., C.C. Giannouli, C. Raparia, S.I. Bastacky, A. Marinov, W. Hawse, R.T. Cattley, J.S. Tilstra, A.M. Campbell, K.M. Nickerson, A. Davidson, and M.J. Shlomchik. 2022. Rubicon promotes clinical and immunological manifestations of SLE in murine models but is not required for LC3-associated phagocytosis (LAP). JCI Insight. https://www.ncbi.nlm.nih.gov/pubmed/35192551
14. Leibler, C., S. John, R.A. Elsner, K.B. Thomas, S. Smita, S. Joachim, R.C. Levack, D.J. Callahan, R.A. Gordon, S. Bastacky, R. Fukui, K. Miyake, S. Gingras, K.M. Nickerson, and M.J. Shlomchik. 2022. Genetic dissection of TLR9 reveals complex regulatory and cryptic proinflammatory roles in mouse lupus. Nat Immunol. 23:1457-69.
15. Smita, S., M. Chikina, M.J. Shlomchik, and J.S. Tilstra. 2022. Heterogeneity and clonality of kidney-infiltrating T cells in murine lupus nephritis. JCI Insight. https://www.ncbi.nlm.nih.gov/pubmed/35271505
16. Weisel, N.M., S.M. Joachim, S. Smita, D. Callahan, R.A. Elsner, L.J. Conter, M. Chikina, D.L. Farber, F.J. Weisel, and M.J. Shlomchik. 2022. Surface phenotypes of naive and memory B cells in mouse and human tissues. Nat Immunol. 23:135-45.
17. Leibler C, John S, Elsner RA, Thomas KB, Smita S, Joachim S, Levack RC, Callahan DJ, Gordon RA, Bastacky S, Fukui R, Miyake K, Gingras S, Nickerson KM, Shlomchik MJ. 2022. Genetic dissection of TLR9 reveals complex regulatory and cryptic proinflammatory roles in mouse lupus. Nature Immunol. 23:1457-69. PMCID: PMC9561083.
18. Luo W, Conter L, Elsner RA, Smita S, Weisel F, Callahan D, Wu Shuxian, Chikina M, Shlomchik M. 2023. IL-21R signal reprogramming cooperates with CD40 and BCR signals to select and differentiate germinal center B cells. Sci Immunol. Feb 24:eadd1823. PMID: 36800413.
19. Nickerson KM, Smita S, Hoehn KB, Marinov AD, Thomas KB, Kos JT, Yang Y, Bastacky SI, Watson CT, Kleinstein SH, Shlomchik MJ. 2023. Age-associated B cells are heterogeneous and dynamic drivers of autoimmunity in mice. J Exp Med.220:e20221346.
- B cells
- Immune Memory
- Autoimmune Disease
- T cell-mediated cancer immunotherapy