Our lab focuses on cell-cell interactions, cellular localization and migration into and within tissues. To address such questions we combine classical immunological assays with cutting edge microscopy including 2-photon imaging of live animals, multicolor staining and 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:
- Function and development cytotoxic CD8+ T cells
- Migration and dynamics of Dendritic Cells within tissues
- Immune defense against viral and bacterial infections
- Interface between innate and adaptive immune system
- Mechanisms of the neuro-immune axis
We are a young dynamic team and based on our technical expertise and broad research interest and are involved in various collaborations with local research teams.
1. Pathogen defense in secondary lymphoid organs
The lymphatic network that transports interstitial fluid and antigens to lymph nodes constitutes 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 sentinel 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 IFN 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 extended 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.)
2. Dynamics of memory CD8+ T cells
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. Effector memory CD8+ T cells reside in peripheral tissue sites of initial pathogen encounter, in apparent anticipation of reinfection. We have shown that within lymph nodes (LNs), memory CD8+ T cells were concentrated near peripheral entry portals of lymph-borne pathogens, promoting rapid engagement of infected sentinel macrophages. A feed-forward CXCL9- dependent circuit provided additional chemotactic cues that further increase local memory cell density. Memory CD8+ T cells also produced effector responses to local cytokine triggers, but their dynamic behavior differed 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 Mar 21;38(3):502-13.)
3. CD4+ T cell help for cytotoxic CD8 responses
Host defense against viruses and intracellular parasites depends on effector CD8+ T cells whose optimal clonal expansion, differentiation, and memory properties require signals from CD4+ T cells. We have addressed the role of dendritic cell (DC) subsets in initial activation of the two T cell types 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; 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 and Göbel et al. Cell in press)
- Eickhoff S, Göbel A, Gerner MY, Klauschen F, Komander K, Hemmi H, Garbi N, Kaisho T, Germain RN, Kastenmüller W. 2015 Robust Anti-viral immunity requires multiple distinct T Cell-Dendritic Cell interactions. Cell in press.
- Franklin BS, Bossaller L, De Nardo D, Ratter JM, Stutz A, Engels G, Brenker C, Nordhoff M, Mirandola SR, Al-Amoudi A, Mangan MS, Zimmer S, Monks BG, Fricke M, Schmidt RE, Espevik T, Jones B, Jarnicki AG, Hansbro PM, Busto P, Marshak-Rothstein A, Hornemann S, Aguzzi A, Kastenmuller W, Latz E. 2014. The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat Immunol: 2014 Aug;15(8):727-37.
- Bald T, Quast T, Landsberg J, Rogava M, Glodde N, Lopez-Ramos D, Kohlmeyer J, Riesenberg S, van den Boorn-Konijnenberg D, Homig-Holzel C, Reuten R, Schadow B, Weighardt H, Wenzel D, Helfrich I, Schadendorf D, Bloch W, Bianchi ME, Lugassy C, Barnhill RL, Koch M, Fleischmann BK, Forster I, Kastenmuller W, Kolanus W, Holzel M, Gaffal E, Tuting T. 2014. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507: 109-13
- Schiwon M, Weisheit C, Franken L, Gutweiler S, Dixit A, Meyer-Schwesinger C, Pohl JM, Maurice NJ, Thiebes S, Lorenz K, Quast T, Fuhrmann M, Baumgarten G, Lohse MJ, Opdenakker G, Bernhagen J, Bucala R, Panzer U, Kolanus W, Grone HJ, Garbi N, Kastenmuller W, Knolle PA, Kurts C, Engel DR. 2014. Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium. Cell 156: 456-68
- Honda T, Egen JG, Lammermann T, Kastenmuller W, Torabi-Parizi P, Germain RN. 2014. Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function in inflamed tissues. Immunity 40: 235-47
- Lammermann T, Afonso PV, Angermann BR, Wang JM, Kastenmuller W, Parent CA, Germain RN. 2013. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498: 371-5
- Kastenmuller W, Brandes M, Wang Z, Herz J, Egen JG, Germain RN. 2013. Peripheral prepositioning and local CXCL9 chemokine-mediated guidance orchestrate rapid memory CD8+ T cell responses in the lymph node. Immunity 38: 502-13
- Kastenmuller W, Torabi-Parizi P, Subramanian N, Lammermann T, Germain RN. 2012. A spatially-organized multicellular innate immune response in lymph nodes limits systemic pathogen spread. Cell 150: 1235-48
- Gerner MY, Kastenmuller W, Ifrim I, Kabat J, Germain RN. 2012. Histo-cytometry: a method for highly multiplex quantitative tissue imaging analysis applied to dendritic cell subset microanatomy in lymph nodes. Immunity 37: 364-76
- Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kastenmuller W, Deming C, Quinones M, Koo L, Conlan S, Spencer S, Hall JA, Dzutsev A, Kong H, Campbell DJ, Trinchieri G, Segre JA, Belkaid Y. 2012. Compartmentalized control of skin immunity by resident commensals. Science 337: 1115-9
- Kastenmuller W, Gasteiger G, Gronau JH, Baier R, Ljapoci R, Busch DH, Drexler I. 2007. Cross-competition of CD8+ T cells shapes the immunodominance hierarchy during boost vaccination. J Exp Med 204: 2187-98
- Kastenmuller W, Kastenmuller K, Kurts C, Seder RA. 2014. Dendritic cell-targeted vaccines - hope or hype? Nat Rev Immunol. 2014 Oct;14(10):705-11.
- Qi H, Kastenmuller W, Germain RN. 2014. Spatiotemporal Basis of Innate and Adaptive Immunity in Secondary Lymphoid Tissue. Annu Rev Cell Dev Biol. 2014;30:141-67.
- Tang J, van Panhuys N, Kastenmuller W, Germain RN. 2013. The future of immunoimaging--deeper, bigger, more precise, and definitively more colorful. Eur J Immunol 43: 1407-12
- Gasteiger G, Kastenmuller W. 2012. Foxp3+ Regulatory T-cells and IL-2: The Moirai of T-cell Fates? Front Immunol 3: 179
- Kastenmuller W, Gerner MY, Germain RN. 2010. The in situ dynamics of dendritic cell interactions. Eur J Immunol 40: 2103-6
- NRW- Rückkehrerprogramm
- Excellence Cluster Immunosensation
- German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)
- Sonderforschungsbereich 670
- Sonderforschungsbereich 704