Our Research

Our goal is to understand the role of stromal-immune and neuro-immune interactions in homeostasis and immunity.

We use multi-disciplinary approaches spanning immunology, neuroscience, cell biology and bioinformatics, harnessing novel tools and advanced imaging to address fundamental challenges that impact human health.

Coordination of immunity by stromal cell networks

Tissues are constructed of a complex microarchitecture that is supported by networks of mesenchymal and endothelial stromal cells. Our work has redefined understanding of the stromal cell architecture in the spleen and revealed dynamic responses by fibroblastic cells in secondary lymphoid organs that are crucial to support adaptive immune responses. We are interested in defining how diverse, anatomically distinct subsets of stromal cells control the outcomes of immunity against infections and cancer.

Stromal cells and regulation of anti-pathogen immunity. We are currently investigating how stromal cell niches control the induction and maintenance of immune responses during acute and persisting virus infections in order to improve immunotherapy of chronic infections.

Tumour-stromal cell interactions in cancer metastasis. We are also investigating how cancer corrupts the healthy functions of stromal cells in lymphoid organs. We are studying the role that these tumour-stroma interactions play in the progression of metastatic disease and how this impacts immune responses that are required for responsiveness to immunotherapies. Our goal is to reveal new therapeutic targets to treat advancing disease in cancer patients.

Selected publications:

  • The transcription factor SpiB regulates the fibroblastic reticular cell network and CD8+ T-cell responses in lymph nodes. Horsnell HL, Cao WH, Belz GT, Mueller SN*, Alexandre YO*. Immunol Cell Biol. 2024 doi: 10.1111/imcb.12740. PMID: 38441326

  • Splenic stromal niches in homeostasis and immunity. Alexandre YO, Mueller SN. Nat Rev Immunol. 2023 23(11):705-719. doi: 10.1038/s41577-023-00857-x. PMID: 36973361

  • A diverse fibroblastic stromal cell landscape in the spleen directs tissue homeostasis and immunity. Alexandre YO, Schienstock D, Lee HJ, Gandolfo LC, Williams CG, Devi S, Pal B, Groom JR, Cao W, Christo SN, Gordon CL, Starkey G, D'Costa R, Mackay LK, Haque A, Ludewig B, Belz GT, Mueller SN. Sci Immunol. 2022 7(67):eabj0641. doi: 10.1126/sciimmunol.abj0641. PMID: 34995096

  • An optimized protocol for the isolation of rare stromal cell populations from the mouse spleen. Alexandre YO, Mueller SN. STAR Protoc. 2022 3(4):101923. doi: 10.1016/j.xpro.2022.101923. PMID: 36595952

  • Systemic Inflammation Suppresses Lymphoid Tissue Remodeling and B Cell Immunity during Concomitant Local Infection. Alexandre YO, Devi S, Park SL, Mackay LK, Heath WR, Mueller SN. Cell Rep. 2020 33(13):108567. doi: 10.1016/j.celrep.2020.108567. PMID: 33378682

  • Infection Programs Sustained Lymphoid Stromal Cell Responses and Shapes Lymph Node Remodeling upon Secondary Challenge. Gregory JL, Walter A, Alexandre YO, Hor JL, Liu R, Ma JZ, Devi S, Tokuda N, Owada Y, Mackay LK, Smyth GK, Heath WR, Mueller SN. Cell Rep. 2017 18(2):406-418. doi: 10.1016/j.celrep.2016.12.038. PMID: 28076785

  • Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Mueller SN, Matloubian M, Clemens DM, Sharpe AH, Freeman GJ, Gangappa S, Larsen CP, Ahmed R. Proc Natl Acad Sci U S A. 2007 104(39):15430-5. doi: 10.1073/pnas.0702579104. PMID: 17878315

  • Regulation of homeostatic chemokine expression and cell trafficking during immune responses. Mueller SN, Hosiawa-Meagher KA, Konieczny BT, Sullivan BM, Bachmann MF, Locksley RM, Ahmed R, Matloubian M. SCIENCE. 2007 317(5838):670-4. doi: 10.1126/science.1144830. PMID: 17673664

Peripheral neuroimmune interactions in host defence

Sympathetic neurotransmitters halt immune cell migration in tissues (Devi et al, 2021)

Communication between the immune system and the nervous system, two supersystems of the body, contributes to homeostasis and responses to disease. Modulation of neuro-immune pathways in tissues using targeted therapies could have an extraordinary impact on diverse diseases. But a better understanding of how immunity in healthy and disease states is regulated by neural pathways is critically needed. Tissues are innervated to varying degrees by sensory and autonomic (sympathetic and parasympathetic) nerves. The Sympathetic nervous system (SNS) controls various body function and also mediates ‘fight or flight’ stress responses that can modulate immune response. We recently discovered a novel mechanism by which the SNS impacts immunity; via dynamic regulation of immune cell motility and functions within tissues. We have also identified a pathway through which immune responses modulate SNS activity during pathogen infections.

Neural regulation of anti-cancer immunity. We are studying how neural signals impact immune responses in the tumour microenvironment and the local lymphoid organs. Our goal is to improve combination therapies to treat cancer. Techniques used in this work include advanced intravital 3-photon imaging and chemogenetic models.

Neuroimmune interactions that shape anti-pathogen immunity. We are studying how immune responses induced by infections can influence the quality and quantity of neural activity. We are defining tissue-specific sympathetic neuronal transcriptomes and functional neuroimmune circuits modulated by infection. Techniques used in this work include retrograde tracing and single cell transcriptomics, tissue clearing and imaging.

Selected publications:

  • Neural control of immune cell trafficking. Mueller SN. J Exp Med. 2022. 219(3):e20211604. doi: 10.1084/jem.20211604. PMID: 35195682

  • Adrenergic regulation of the vasculature impairs leukocyte interstitial migration and suppresses immune responses. Devi S, Alexandre YO, Loi JK, Gillis R, Ghazanfari N, Creed SJ, Holz LE, Shackleford D, Mackay LK, Heath WR, Sloan EK, Mueller SN. Immunity. 2021 54(6):1219-1230.e7. doi: 10.1016/j.immuni.2021.03.025. PMID: 33915109

Intravital imaging and analysis of immune dynamics

We have developed world-class microscopes and techniques for intravital imaging, including a new 3-photon microscope to investigate how immune cells behave in vivo. The technique generates 4D timelapse data (3D in space, 1D in time), which enables us to visualise dense 3D tissue environments and the migratory behaviours of individual immune cells.

Imaging tissue-resident memory T cell responses in mice and humans. We have extensive experience using intravital multi-photon microscopy to investigate tissue-resident memory T (Trm) cells in tissues including the skin. We recently identified Trm cells in the cornea of the eyes in mice. With collaborators Drs Laura Downie and Holly Chinnery we also developed a novel method to image the cornea in humans, and discovered that immune cells present in healthy eyes include tissue-resident T lymphocytes. This has opened up exciting avenues to use intravital imaging in people to learn about the human immune system in health and disease. Such experiments are geared towards fundamental knowledge generation and discovery of new therapies.

 

Development of powerful, flexible, open image analysis software: Cecelia. Quantitative analysis of complex static (2D and 3D) and dynamic (4D) images often relies upon several disconnected software packages and/or the use of expensive commercial software packages. We have recently developed a software package for the complete analysis of all types of biological imaging data. The goal of Cecelia is to simplify image analysis for biologists within a single user interface that is built around Shiny and napari: Find Cecelia on Github.

To better analyse immune cell dynamics in complex tissue microenvironments, which is currently limited by a lack of accurate and reliable cell segmentation options, we are also investigating new deep learning approaches to track immune cell migration in vivo.

Selected publications:

  • Redefining the human corneal immune compartment using dynamic intravital imaging. Downie LE*, Zhang X, Wu M, Karunaratne S, Loi JK, Senthil K, Arshad S, Bertram K, Cunningham AL, Carnt N, Mueller SN*, Chinnery HR*. Proc Natl Acad Sci U S A. 2023 120(31):e2217795120. doi: 10.1073/pnas.2217795120. PMID: 37487076

  • Corneal tissue-resident memory T cells form a unique immune compartment at the ocular surface. Loi JK, Alexandre YO, Senthil K, Schienstock D, Sandford S, Devi S, Christo SN, Mackay LK, Chinnery HR, Osborne PB, Downie LE, Sloan EK, Mueller SN. Cell Rep. 2022 39(8):110852. doi: 10.1016/j.celrep.2022.110852. PMID: 35613584 

  • Moving beyond velocity: Opportunities and challenges to quantify immune cell behavior. Schienstock D, Mueller SN. Immunol Rev. 2022 306(1):123-136. doi: 10.1111/imr.13038. PMID: 34786722

  • Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses. Park SL, Zaid A, Hor JL, Christo SN, Prier JE, Davies B, Alexandre YO, Gregory JL, Russell TA, Gebhardt T, Carbone FR, Tscharke DC, Heath WR, Mueller SN*, Mackay LK*. Nat Immunol. 2018 19(2):183-191. doi: 10.1038/s41590-017-0027-5.  PMID: 29311695

  • Chemokine Receptor-Dependent Control of Skin Tissue-Resident Memory T Cell Formation. Zaid A, Hor JL, Christo SN, Groom JR, Heath WR, Mackay LK, Mueller SN. J Immunol. 2017 199(7):2451-2459. doi: 10.4049/jimmunol.1700571. PMID: 28855310

  • Tissue-resident memory T cells: local specialists in immune defence. Mueller SN*, Mackay LK. Nat Rev Immunol. 2016 16(2):79-89. doi: 10.1038/nri.2015.3. PMID: 26688350

  • Spatiotemporally Distinct Interactions with Dendritic Cell Subsets Facilitates CD4+ and CD8+ T Cell Activation to Localized Viral Infection. Hor JL, Whitney PG, Zaid A, Brooks AG, Heath WR, Mueller SN. Immunity. 2015 43(3):554-65. doi: 10.1016/j.immuni.2015.07.020. PMID: 26297566

  • Persistence of skin-resident memory T cells within an epidermal niche. Zaid A, Mackay LK, Rahimpour A, Braun A, Veldhoen M, Carbone FR, Manton JH, Heath WR, Mueller SN. Proc Natl Acad Sci U S A. 2014 111(14):5307-12. doi: 10.1073/pnas.1322292111. PMID: 24706879

  • Different patterns of peripheral migration by memory CD4+ and CD8+ T cells.  Gebhardt T, Whitney PG, Zaid A, Mackay LK, Brooks AG, Heath WR, Carbone FR, Mueller SN. Nature. 2011 477(7363):216-9. doi: 10.1038/nature10339. PMID: 21841802