Leukocyte Dynamics (Kastenmüller Lab)

Our lab focuses on cell-cell interactions, cellular localization and migration between and within tissues. To address such questions we combine classical immunological assays like multicolour flow cytometry with cutting edge microscopy including 2-photon imaging of live animals, confocal analysis of tissue section and whole mount preparations to study cellular immune responses in the context of infections. Central questions currently addressed in our lab include:

1. Function and development cytotoxic CD8+ T cells
2. Migration and dynamics of Dendritic Cells within tissues
3. Immune defense against viral and bacterial infections
4. Interface between innate and adaptive immune system
5. Intercellular communication
6. Development of new animal model

We are a young dynamic team and with a high technical expertise and a broad research interest. We are involved in various collaborations with national and international research teams.

The lymphatic network that transports interstitial fluid and antigens to lymph nodes forms a conduit system that can be hijacked by invading pathogens to achieve systemic spread unless dissemination is blocked in the lymph node itself. We found that a network of diverse lymphoid cells (natural killer cells, gd T cells, natural killer T cells, and innate-like CD8+ T cells) are spatially prepositioned close to lymphatic sinus-lining macrophages where they can rapidly and efficiently receive inflammasome-generated IL-18 and additional cytokine signals from the pathogen-sensing phagocytes. This leads to rapid IFNg secretion by the strategically positioned innate lymphocytes, fostering antimicrobial resistance in the macrophage population. Interference with this innate immune response loop allows systemic spread of lymphborne bacteria. Our findings extends our understanding of the functional significance of cellular positioning and local intercellular communication within lymph nodes while emphasizing the role of these organs as highly active locations of innate host defense.

(Kastenmüller W et al. Cell. 2012 Sep 14;150(6):1235-48. Gasteiger G et al. Immunol Rev. 2016 May;271(1):200-20)

After an infection, the immune system generates long-lived memory lymphocytes whose increased frequency and altered state of differentiation enhance host defense against reinfection. The spatial distribution of memory cells was found to contribute to their protective function. Tissue-resident memory CD8+ T cells reside in peripheral tissue at sites of initial pathogen encounter. We have shown that within lymph nodes (LNs), memory CD8+ T cells are also concentrated near peripheral entry portals of lymph-borne pathogens, promoting rapid engagement of infected sinus-lining macrophages. A feed-forward CXCL9- dependent circuit provides additional chemotactic cues that further increase local memory T cell density. Memory CD8+ T cells also produce effector responses to local cytokine triggers, but their dynamic behavior differe from that seen after antigen recognition. We have revealed the distinct localization and dynamic behavior of naive versus memory T cells within LNs and how these differences contribute to host defense.

(Kastenmuller W et al. Immunity. 2013 Mär 21;38(3):502-13, Qi et al. Annu Rev Cell Dev Biol. 2014;30:141-67.)

Host defense against viruses and intracellular parasites depends on effector CD8⁺ T cells whose optimal clonal expansion, differentiation, and memory properties require helper signals from CD4⁺ T cells. We have addressed the role of dendritic cell (DC) subsets in initial activation of the two T cell types (CD4 and CD8 T cells) and their co-operation. Surprisingly, initial priming of CD4⁺ and CD8⁺ T cells was spatially segregated within the lymph node and occurred on different DC with temporally distinct patterns of antigen-presentation via MHCI vs. MHCII molecules. DC that co-present antigen via both MHC molecules were detected at a later stage (>24h post infection); these XCR1⁺-DC are the critical platform involved in CD4⁺ T cell augmentation of CD8⁺ T cell responses. With these findings we delineated the complex choreography of cellular interactions underlying effective cell-mediated anti-viral responses, with implications for basic DC subset biology as well as for translational application to the development of vaccines that evoke optimal T cell immunity.

(Eickhoff S et al. Cell 2015 Sep 10;162(6):1322-37 und Borst J. et al. Nat Rev. Immunol. 2018 Jul 29.)

Kastenmueller link pubmed: https://pubmed.ncbi.nlm.nih.gov

Selected Articles

1. Resident regulatory T cells reflect the immune history of individual lymph nodes. Kaminski A, Hager FT, Kopplin L, Ticconi F, Leufgen A, Vendelova E, Rüttger L, Gasteiger G, Cerovic V, Kastenmüller W, Pabst O, Ugur M. Published in Science Immunology 2023. DOI: 10.1126/sciimmunol.adj5789
2. Lymph node medulla regulates the spatiotemporal unfolding of resident dendritic cell networks. Ugur M, Labios RJ, Fenton C, Knöpper K, Jobin K, Imdahl F, Golda G, Hoh K, Grafen A, Kaisho T, Saliba AE, Grün D, Gasteiger G, Bajénoff M, Kastenmüller W., Immunity. 2023 Aug 8;56(8):1778-1793.e10. doi: 10.1016/j.immuni.2023.06.020. Epub 2023 Jul 17.
3. CD4⁺ T cell-induced inflammatory cell death controls immune-evasive tumours, Bastian Kruse,  Anthony C. Buzzai, Naveen Shridhar, Andreas D. Braun, Susan Gellert, Kristin Knauth, Joanna Pozniak, Johannes Peters, Paulina Dittmann, Miriam Mengoni, Tetje Cornelia van der Sluis, Simon Höhn, Asier Antoranz, Anna Krone, Yan Fu, Di Yu, Magnus Essand, Robert Geffers, Dimitrios Mougiakakos, Sascha Kahlfuß, Hamid Kashkar, Evelyn Gaffal, Francesca M. Bosisio, Oliver Bechter, Florian Rambow, Jean-Christophe Marine, Wolfgang Kastenmüller, Andreas J. Müller & Thomas Tüting, nature. 2023; June 14; doi: 10.1038/s41586-023-06199-x
4. Lymphatic migration of unconventional T cells promotes site-specific immunity in distinct lymph nodes. Ataide MA, Knöpper K, Cruz de Casas P, Ugur M, Eickhoff S, Zou M, Shaikh H, Trivedi A, Grafen A, Yang T, Prinz I, Ohlsen K, Gomez de Agüero M, Beilhack A, Huehn J, Gaya M, Saliba AE, Gasteiger G, Kastenmüller W, Immunity. 2022 Aug 17:S1074-7613(22)00354-5. ; doi: 10.1016/j.immuni.2022.07.019
5. Type 1 conventional dendritic cells maintain and guide the differentiation of precursors of exhausted T cells in distinct cellular niches. Dähling S, Mansilla AM, Knöpper K, Grafen A, Utzschneider DT, Ugur M, Whitney PG, Bachem A, Arampatzi P, Imdahl F, Kaisho T,  Zehn D, Klauschen F, Garbi N, Kallies A,  Saliba AE, Gasteiger G, Bedoui S, Kastenmüller W. Immunity. 2022 Apr 12; 55(4):656-670.e8 ; doi: 10.1016/j.immuni.2022.03.006
6. BATF3 programs CD8+ T cell memory. Ataide MA, Komander K, Knöpper K, Peters AE, Wu H, Eickhoff S, Gogishvili T, Weber J, Grafen A, Kallies A, Garbi N, Einsele H, Hudecek M, Gasteiger G, Hölzel M, Vaeth M, Kastenmüller W. Nat Immunol. 2020 Nov;21(11):1397-1407. doi: 10.1038/s41590-020-0786-2.Open Access
7. Lymphatic Endothelial Cells Are Essential Components of the Subcapsular Sinus Macrophage Niche. Mondor I, Baratin M, Lagueyrie M, Saro L, Henri S, Gentek R, Suerinck D, Kastenmuller W, Jiang JX, Bajénoff M. Immunity. 2019 Jun 18;50(6):1453-1466.e4. doi: 10.1016/j.immuni.2019.04.002
8. Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis. Welz M, Eickhoff S, Abdullah Z, Trebicka J, Gartlan KH, Spicer JA, Demetris AJ, H. Akhlaghi H, Anton M, Manske K, Zehn D, Nieswandt B, Kurts C, Trapani JA, Knolle P, Wohlleber D, Kastenmüller W. Nat Comm 2018 Nov 15;9(1):4805. doi: 10.1038/s41467-018-07213-x.
9. CD8+ T Cells Orchestrate pDC-XCR1+ Dendritic Cell Spatial and Functional Cooperativity to Optimize Priming. Brewitz A, Eickhoff S, Dähling S, Quast T, Bedoui S, Kroczek RA, Kurts C, Garbi N, Barchet W, Iannacone M, Klauschen F, Kolanus W, Kaisho T, Colonna M, Germain RN, Kastenmüller W. Immunity 2017 Feb 21;46(2):205-219. doi: 10.1016/j.immuni.2017.01.003.
10. Robust Anti-viral Immunity Requires Multiple Distinct T Cell-Dendritic Cell Interactions. Eickhoff S, Brewitz A, Gerner MY, Klauschen F, Komander K, Hemmi H, Garbi N, Kaisho T, Germain RN, Kastenmüller W. Cell 2015 Sep 10;162(6):1322-37. doi: 10.1016/j.cell.2015.08.004.

Selected Review Articles

1. Concepts of GPCR-controlled navigation in the immune system. Lämmermann T, Kastenmüller W. Immunol Rev. 2019 May;289(1):205-231. doi: 10.1111/imr.12752
2. CD4+ T cell help in cancer immunology and immunotherapy. Borst J, Ahrends T, Bąbała N, Melief CJM, Kastenmüller W. Nat Rev Immunol. 2018 Oct;18(10):635-647. doi: 10.1038/s41577-018-0044-0.
3. Lymph node - an organ for T-cell activation and pathogen defense. Gasteiger G, Ataide M, Kastenmüller W. Immunol Rev. 2016 May;271(1):200-20. doi: 10.1111/imr.12399.
4. Dendritic cell-targeted vaccines - hope or hype? Kastenmuller W, Kastenmuller K, Kurts C, Seder RA. 2014. Nat Rev Immunol 2014 Oct;14(10):705-11. doi: 10.1038/nri3727.
5. Spatiotemporal Basis of Innate and Adaptive Immunity in Secondary Lymphoid Tissue. Qi H, Kastenmuller W, Germain RN. 2014. Annu Rev Cell Dev Biol 2014;30:141-67. doi: 10.1146/annurev-cellbio-100913-013254.
6. Foxp3+ Regulatory T-cells and IL-2: The Moirai of T-cell Fates? Gasteiger G, Kastenmuller W.. Front Immunol 2012 3: 179. doi: 10.3389/fimmu.2012.00179.

ERC Consolidator Grant: Spatio-temporal regulation of T cell priming