Cellular Immunology

Immune-mediated diseases, such as autoimmunity, allergies or chronic inflammation of various organ systems, are on the rise. Here, the immune system, which protects us from infections, mistakenly attacks harmless “antigens”, such as plant pollen or food, the body’s own structures and cells or the microbiota. The exact causes of these diseases are mostly unknown and vary from disease to disease and probably even from patient to patient. The immune cells that initiate or prevent these immune reactions are poorly characterized. For patients, this means that in the absence of detailed knowledge about the disease-causing cells, the immune system is therapeutically suppressed, usually for life and with adverse side effects. Symptoms are targeted instead of the disease cause. Our goal is tailor-made diagnostics and therapies, through the precise characterization of the disease-causing immune cells.

T helper (Th) cells organize the immune response specifically adapted to each antigen. Unwanted reactions against harmless antigens are actively suppressed by specialized regulatory T cells (Treg). If control is defective, pathogenic, pro-inflammatory effector T cells expand. Shutting down the disease by restoring natural antigen-specific control is ourtherapeutic goal.

For this purpose, we have developed sensitive methods to identify antigen-specific Th cells in humans that are relevant for the different diseases. This makes it possible to detect the cellular and molecular cause of specific immune pathologies and to target them therapeutically or to use them as diagnostic parameters. We have pursued this approach in a wide variety of disease situations, such as COVID-19, allergies, tuberculosis, invasive fungal infections, and autoimmunity. Based on these results, we are working on new antigen-specific diagnostic and therapeutic options to eliminate causes of disease.

• Characterization of the immune response against harmless antigens
• T cell response against tumor-associated and tumor–neoantigens
• Antigen-specific T cells for infection diagnostics
• Human Tregs: antigen specificity, functionality, Treg-based therapies
• Molecular regulation of anti-inflammatory effector functions in T cells

1. The pre-exposure SARS-CoV-2-specific T cell repertoire determines the quality of the immune response to vaccination

Saggau C, Martini GR, Rosati E, Meise S, Messner B, Kamps AK, Bekel N, Gigla J, Rose R, Voß M, Geisen UM, Reid HM, Sümbül M, Tran F, Berner DK, Khodamoradi Y, Vehreschild MJGT, Cornely O, Koehler P, Krumbholz A, Fickenscher H, Kreuzer O, Schreiber C, Franke A, Schreiber S, Hoyer B, Scheffold A, Bacher P. Immunity. 2022 Aug 12;S1074-7613(22)00396-X.  doi: 10.1016/j.immuni.2022.08.003. Online ahead of print.

2. M ycobacterium tuberculosis-specific CD4 T-cell scoring discriminates tuberculosis infection from disease

Mantei A, Meyer T, Schürmann M, Beßler C, Bias H, Krieger D, Bauer T, Bacher P, Helmuth J, Volk HD, Schürmann D, Scheffold A, Meisel C. Eur Respir J. 2022 Jul 28;60(1):2101780. doi: 10.1183/13993003.01780-2021. Print 2022 Jul.

3. A Notch/STAT3-driven Blimp-1/c-Maf-dependent molecular switch induces IL-10 expression in human CD4+ T cells and is defective in Crohn´s disease patients

Ahlers J, Mantei A, Lozza L, Stäber M, Heinrich F, Bacher P, Hohnstein T, Menzel L, Yüz SG, Alvarez-Simon D, Bickenbach AR, Weidinger C, Mockel-Tenbrinck N, Kühl AA, Siegmund B, Maul J, Neumann C, Scheffold A. Mucosal Immunol. 2022. doi: 10.1038/s41385-022-00487-x.

4. Low avidity CD4+ T cell responses to SARS-CoV-2 in unexposed individuals and humans with severe COVID-19

Bacher P, Rosati E, Esser D, Rios-Martini G, Saggau C, Schiminsky E, Dargvainiene J, Schöder I, Wieters I, Khodamoradi Y, Eberhardt F, Vehreschild MJGT, Neb H, Sonntagbauer M, Conrad C, Tran F, Rosenstiel P, Markewitz R, Wandinger, K-P, Augustin M, Rybniker J, Kochanek M, Leypoldt F, Cornely OA, Koehler P, Franke A, Scheffold A. Immunity 2020. 53(6):1258-1271.e5

5. Human Anti-fungal Th17 Immunity and Pathology Rely on Cross-Reactivity against Candida albicans

Bacher P, Hohnstein T, Beerbaum E, Röcker M, Blango MG, Kaufmann S, Röhmel J, Eschenhagen P, Grehn C, Seidel K, Rickerts V, Lozza L, Stervbo U, Nienen M, Babel N, Milleck J, Assenmacher M, Cornely OA, Ziegler M, Wisplinghoff H, Heine G, Worm M, Siegmund B, Maul J, Creutz P, Tabeling C, Ruwwe-Glösenkamp C, Sander LE, Knosalla C, Brunke S, Hube B, Kniemeyer O, Brakhage AA, Schwarz C, Scheffold A. Cell. 2019; 176(6):1340-1355.e15.

6. c-Maf-dependent T_reg cell control of intestinal T_H17 cells and IgA establishes host-microbiota homeostasis

Neumann C, Blume J, Roy U, Teh PP, Vasanthakumar A, Beller A, Liao Y, Heinrich F, Arenzana TL, Hackney JA, Eidenschenk C, Gálvez EJC, Stehle C, Heinz GA, Maschmeyer P, Sidwell T, Hu Y, Amsen D, Romagnani C, Chang HD, Kruglov A, Mashreghi MF, Shi W, Strowig T, Rutz S, Kallies A, Scheffold A.Nat Immunol. 2019 Apr;20(4):471-481. doi: 10.1038/s41590-019-0316-2. Epub 2019 Feb 18.PMID: 30778241

7. Regulatory T Cell Specificity Directs Tolerance versus Allergy against Aeroantigens in Humans

Bacher P, Heinrich F, Stervbo U, Nienen M, Vahldieck M, Iwert C, Vogt K, Kollet J, Babel N, Sawitzki B, Schwarz C, Bereswill S, Heimesaat MM, Heine G, Gadermaier G, Asam C, Assenmacher M, Kniemeyer O, Brakhage AA, Ferreira F, Wallner M, Worm M, Scheffold A.Cell. 2016 Nov 3;167(4):1067-1078.e16. doi: 10.1016/j.cell.2016.09.050. Epub 2016 Oct 20.PMID: 27773482

8. Role of Blimp-1 in programing Th effector cells into IL-10 producers

Neumann C, Heinrich F, Neumann K, Junghans V, Mashreghi MF, Ahlers J, Janke M, Mockel-Tenbrinck N, Kühl A, Heimesaat M, Esser C, Im SH, Radbruch A, Rutz S and Scheffold A. J Exp Med. 2014 211(9):1807-19.

Prof. Dr. rer. nat. Alexander Scheffold

• PUBLONS
• ORCID

DFG

• The role of the transcription factor c-Maf for the control of mucosal inflammation in the intestine.
• Establishment of a human antigen-specific CD4 T cell atlas (with P. Bacher & A. Franke, IKMB)
• SFB/Transregio 241: Immune-Epithelial Signalling Pathways in Inflammatory Bowel Disease, Subproject B07: Identification and functional characterization of human microbiota-specific regulatory T cells.
• SFB 877: Proteolysis as a regulatory event in pathophysiology. Project B15:Proteolyticmodulation of intestinal CD4 T helper cell function and immune homeostasis
• SFB 1526: „Pathomechansims of autoantibody-mediated autoimmune disease(PANTAU): insights from pemphigoid diseases“ Project A01: Autoreactive T cells in pemphigoid diseases
• Exzellenzcluster „Precision Medicine in Chronic Inflammation“ (PMI) (EXC 2167-390884018) TI-2 & RTF IV
• Klinische Forschergruppe: Towards a Cure for Adults and Children with Acute Lymphoblastic Leukemia (ALL) CATCH-ALL, Project P5: The Yin and Yang of anti-cancer CD4+ T cell responses in ALL

BMBF:

• InfectControl 2020 – Verbundvorhaben: Innovative Antigen-spezifische Diagnostik für Pathogen-assoziierte Erkrankungen AnDiPath
• European Joint Program for Rare Diseases (EJPRD): Autoantigen-specific T cells in neuromyelitis optica (AspecT-NMO): Coordinator Alexander Scheffold

• Derk Amsen, Sanquin, Amsterdam, Netherlands
• Mario Assenmacher & Michael Apel, Miltenyi Biotec GmbH, Bergisch Gladbach, Deutschland
• Axel Brakhage & Olaf Kniemeyer, Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie (HKI), Jena, Germany
• Oliver Cornely, Klinik I für Innere Medizin, Uniklinik Köln, Köln, Deutschland
• Eran Elinav, Weizman Institute of Science, Rehovot, Israel
• Simon Fillatreau, Institut d´enfant malade Necker (INEM), Paris, France
• Friedemann Paul, Charité-Universitätsmedizin Berlin, Germany
• Roland Martin, University of Zurich, Zurich, Switzerland
• Sascha Rutz, Genentech, San Francisco, USA
• Britta Siegmund, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie CBF, Charité – Universitätsmedizin Berlin, Berlin, Deutschland