My research interests are T cells and T cell receptor (TCR) signaling; in particular in the context of differentiation and suppression mechanisms of human regulatory T cells (Tregs).
Tregs are important mediators of immune tolerance and may be therapeutically exploited in the future for treatment of autoimmune and inflammatory diseases as well as cancer, yet the molecular details of Treg generation and their suppression mechanisms are incompletely understood.
The goal of my research in CMM is to combine my experimental biology/immunology background with the CompMed group’s expertise in high throughput techniques and computational integration of the data applied to (i) differentiation of induced Tregs (iTregs) as well as to (ii) mechanisms of suppression of conventional T cells by Tregs.
(i) We compared several established and new protocols to induce human iTregs from naive T cells (Schmidt et al. PLoSOne 2016). We recently performed molecular profiling during Treg induction over time using RNA-sequencing and high-resolution proteomics. Based on integrative analysis of these data, in collaboration with Ass. Prof. Francesco Marabita, we predicted several "candidate molecules" to be novel regulators of Tregs. In a targeted shRNA screen, during a visiting research stay in Anjana Rao's Lab in La Jolla, knockdown of several of those "candidate molecules" indeed had an impact on Treg induction that is, reduced expression of the "master" Treg transcription factor FOXP3. These molecules will be followed-up in detail regarding their molecular mechanisms and disease relevance.
(ii) We previously found that Tregs can rapidly suppress certain TCR signaling pathways in conventional T cells, leading to suppression of effector cytokine expression (Schmidt et al. Science Signaling 2011). To gain a more global picture of changes occurring in conventional T cells during suppression by Tregs, we are performing phosphoproteomics and subcellular proteomics. We found that Tregs globally decreased TCR-induced phosphorylations in Tcons, and several novel phosphoproteins are currently validated regarding their funtional role in T cell suppression. This project is majorly driven by Rubin Joshi, PhD student in our group.
• Schmidt A, Rieger CC, Venigalla RK, Éliás S, Max R, Lorenz HM, Gröne HJ, Krammer PH, Kuhn A: Analysis of FOXP3+ regulatory T cell subpopulations in peripheral blood and tissue of patients with systemic lupus erythematosus. Immunologic Research in press.
• Éliás S, Schmidt A, Kannan V, Andersson J, Tegnér J (2016): TGF-β Affects the Differentiation of Human GM-CSF+ CD4+ T Cells in an Activation- and Sodium-Dependent Manner. Frontiers in Immunology. PMID 28066414.
• Schmidt A, Éliás S, Joshi RN, Tegnér J (2016): In Vitro Differentiation of Human CD4+FOXP3+ Induced Regulatory T Cells (iTregs) from Naïve CD4+ T Cells Using a TGF-β-containing Protocol. Journal of Visualized Experiments. PMID 28060341.
• Schmidt A, Zhang XM, Joshi RN, Iqbal S, Wahlund C, Gabrielsson S, Harris R, Tegnér J (2016): Human macrophages induce CD4+Foxp3+ regulatory T cells via binding and re-release of TGF-β. Immunology & Cell Biology. PMID 27075967.
• Schmidt A, Eriksson M, Shang MM, Weyd H, Tegnér J (2016): Comparative Analysis of Protocols to Induce Human CD4+Foxp3+ Regulatory T Cells by Combinations of IL‐2, TGF‐beta, Retinoic Acid, Rapamycin and Butyrate. PLoS ONE 11(2): e0148474. doi:10.1371/journal.pone.0148474
• Roci I, Gallart-Ayala H, Schmidt A, Watrous J, Jain M, Wheelock CE, Nilsson R (2016): Metabolite profiling and stable isotope tracing in sorted subpopulations of mammalian cells. Anal Chem. 2016 Feb 8. [Epub ahead of print]. doi: 10.1021/acs.analchem.5b04071
• Gustafsson-Sheppard N, Jarl L, Mahdessian D, Strittmatter L, Schmidt A, Madhusudan N, Tegnér J, Käll-Lundberg E, Jain M, Nilsson R (2015): The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation. Sci Rep. 5:15029. doi: 10.1038/srep15029.
• Zenil H, Schmidt A, Tegnér J (2015): Causality, Information and Biological Computation: An algorithmic software approach to life, disease and the immune system. Invited Book chapter contribution to Information and Causality: From Matter to Life. Sara I. Walker, Paul C.W. Davies and George Ellis (eds.), Cambridge University Press. arXiv:1508.06538
• Schmidt A, Oberle N, Krammer PH (2012): Molecular mechanisms of Treg-mediated T cell suppression. Review article. Frontiers in Immunology (Frontiers in T Cell Biology) 3:51, 1-20.
• Schmidt A, Oberle N, Weiss EM, Vobis D, Frischbutter S, Baumgrass R, Falk CS, Haag M, Brügger B, Lin H, Mayr GW, Reichardt P, Gunzer M, Suri-Payer E, Krammer PH (2011): Human regulatory T cells rapidly suppress T cell receptor–induced Ca2+, NF-κB, and NFAT signaling in conventional T cells. Science Signaling 4, ra90.
• Haag M, Schmidt A, Sachsenheimer T, Brügger B (2012): Quantification of signaling lipids by Nano-Electrospray Ionization Tandem Mass Spectrometry (Nano-ESI MS/MS). Metabolites 2, 57-76.
• Weiss EM, Schmidt A, Vobis D, Garbi N, Lahl K, Mayer CT, Sparwasser T, Ludwig A, Suri-Payer E, Oberle N, Krammer PH (2011): Foxp3-mediated suppression of CD95L expression confers resistance to activation-induced cell death in regulatory T cells. The Journal of Immunology 187(4):1684-1691.
• Heid JB, Schmidt A, Oberle N, Goerdt S, Krammer PH, Suri-Payer E, Klemke CD (2009): FOXP3+CD25− tumor cells with regulatory function in Sézary syndrome. Journal of Investigative Dermatology 129:2875–2885.
Albert Heck & Nadine Binai, University of Utrecht, Netherlands.
Janne Lehtiö & Henrik Johansson, SciLifeLab, Stockholm, Sweden.
Anjana Rao, La Jolla Institute for Allergy & Immunology, San Diego, USA.
Robert Harris & Xingmei Zhang, CMM, Stockholm, Sweden.
Susanne Gabrielsson & Casper Wahlund, Karolinska Institute, Stockholm, Sweden.
Ioannis Tsamardinos, University of Crete, Heraklion, Greece.
Anne Kuhn, DKFZ Heidelberg and IZKS Mainz, Germany.
Roland Nilsson, CMM, Stockholm, Sweden.