Joint research group of Professor Bernhard Moser and Professor Matthias Eberl at the Division of Infection and Immunity.
Our research focuses on tissue-resident immune cells during homeostasis and on the recruitment of effector cells to the site of inflammation.
Current grant support
- EU Horizon 2020, Marie Skłodowska-Curie Individual Fellowship (to Dr. Loic Raffray)
- Life Sciences Bridging Fund Wales, Pathfinder Grant
- Medical Research Council research grant
- Health and Care Research Wales, Clinical Research Time Award (to Dr. Matt Morgan)
- MRC PhD Studentship (to Amy Brook and Ariadni Kouzeli)
- Tenovus PhD Studentship (to Teja Rus)
- Health and Care Research Wales, Wales Cancer Research Centre project grant
Since establishing our research group at Cardiff University we have raised more than £4.5m of funding from the Medical Research Council, Wellcome Trust, Cancer Research UK, Kidney Research UK, Tenovus, European Commission FP7, National Institute of Health Research (NIHR), Health and Care Research Wales/Welsh Government and other organisations.
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Immune fingerprints in acute infection
Treating infection in the face of a global spread of antimicrobial resistance is one of the greatest challenges of the 21st century. However, there remains a lack of appreciation of how the body senses and fights different bacterial pathogens.
Our research aims to explore and exploit the pathophysiological events underlying pathogen-specific inflammatory responses for diagnostic and therapeutic purposes. The immune system has evolved to survey the body constantly for potentially hazardous structures. Different pathogens express different molecular patterns and hence interact uniquely with distinct components of the immune system. The type of infection is therefore likely to evoke distinct immunological signatures, or ‘immune fingerprints’, that can be assessed quantitatively and qualitatively.
A prime example for this discrimination of different pathogens is the unique responsiveness of unconventional T cells to common microbial metabolites that are shared by many bacterial pathogens but are absent from human cells. γδ T cells and MAIT cells are rapidly drawn to sites of acute infection, where they will encounter invading microbes in the context of other immune cells, mainly neutrophils and monocytes, and the surrounding tissue.
Our findings indicate that in early infection this interplay will attract further effector cells, enhance the activity of scavenger cells and promote the development of microbe-specific immunity. However, if triggered at the wrong time or the wrong site, this reaction may lead to inflammation-related damage and affect patient outcomes. The centre stage unconventional T cells take in orchestrating inflammatory cascades in microbial infections identifies these cells as prime targets for novel treatments and diagnostics.
We are aiming to define local and systemic pathogen-specific signatures of soluble and cellular immune biomarkers in diseases where early and targeted intervention is key and where clinical outcomes will benefit from better and earlier diagnostics. We are studying individuals presenting with peritoneal dialyis-related peritonitis, acute sepsis, urinary tract infection and ventriculitis, in collaborations with clinicians, microbiologists, statisticians and commercial partners.
Cellular immunotherapy offers novel, safe and effective routes to treating cancer and autoimmunity. However, approaches utilising conventional T cells are hampered by the need to identify suitable target antigens that are expressed by tumour cells but not healthy tissues, and that are recognized with sufficient affinity. Most importantly, the applicability of conventional T-cell based therapies is governed by the MHC restriction of tumour-specific epitopes, thereby limiting the potential benefit to patients carrying the appropriate MHC haplotype.
Alternative approaches exploit non-MHC-restricted γδ T cells that recognize stress-induced changes in transformed cells. γδ T cells combine adaptive features, including the expression of re-arranged T-cell receptors, with innate-like functions reminiscent of those of NK cells and even myeloid cells. Most γδ T cells also express NKG2D and other NK receptors, which allow them to recognise a broad range of stressed and transformed cells in a TCR-independent fashion. γδ T cells are thus well equipped to recognize a wide range of targets, and can deliver a deadly cocktail of cytotoxic effector molecules.
Intriguingly, our work has demonstrated that γδ T cells are able to take up soluble proteins and cell debris, including material released from lysed cells, load these antigens onto MHC class I molecules via a proteasome-dependent cross-presentation pathway, and thereby directly prime antigen-specific CD8+ T cells. In addition, activated γδ T cells present MHC II-restricted antigens to CD4+T cells and modulate the polarisation of T helper cells towards functionally distinct subsets including Th1 and Th22 cells. In addition, γδ T cells interact with monocytes, neutrophils and dendritic cells and promote their differentiation and maturation into effective antigen-presenting cells, thereby indirectly augmenting conventional T-cell responses. Taken together, these observations lead to the attractive possibility that γδ T-cell based immunotherapies would not only result in non-MHC-restricted killing of many different targets but concomitantly yield antigen-specific and MHC-restricted CD4+ and CD8+ T cells that could mount a second wave of cytotoxic insult on the tumour.
Our current interest focuses on: the molecular mechanisms underlying the generation of γδ T-APCs the mechanisms describing antigen uptake/processing γδ T-cells the physiological relevance of γδ T-APCs in human adaptive immunity the sensitisation of tumour cells to γδ T-cell mediated killing
Peripheral immune surveillance
Healthy peripheral tissues, such as the skin, lungs and digestive tract, are not “silent” in terms of immunological processes. In fact, healthy peripheral tissues are equipped with an intricate immune surveillance system that is essential for infection control and tissue integrity. Human skin harbours large numbers of T cells - approximately 2x10(10), twice as many as circulating T cells present in peripheral blood. But local T cells are just one part of the very complex local immune surveillance system that includes cells of both the innate and adaptive immune system:
- How immune surveillance cells interact with each other is not clear.
- We do not know how they are being generated and maintained.
- We need to investigate how they respond to local challenges.
- We need to determine whether these immune surveillance cells contribute to local inflammatory diseases.
We address these questions by studying the migration properties of immune surveillance cells defined by the cell surface composition of chemokine receptors and adhesion molecules.
Our current work is largely guided by the chemokine paradigm that links immune cell localisation with its function. In order words, the cellular address code (chemokine receptors, adhesion molecules) reflects the destiny, including tissue tropism and function, of a particular type of immune cell. Accordingly, effector cells that express receptors for inflammatory chemokines are attracted to sites of inflammation where the corresponding inflammatory chemokines are being produced. We feel that this paradigm also applies to the immune surveillance system in healthy peripheral tissues.
Our current investigations focus on the immune surveillance cells present in human skin and address the following two topics:
- Peripheral immune surveillance T cells (TPS cells)
Our findings demonstrate that the chemokine receptor CCR8 is broadly expressed on skin TPS cells suggesting that this chemokine receptor and its skin-expressed ligand CCL1 are involved in the localisation of long-lasting memory T cells in healthy human skin. We are currently studying CCR8/CCL1 chemokine system humans and mice.
- Tissue-homing myeloid cells
Peripheral tissue myeloid cells comprise monocyte-derived macrophages and dendritic cells that are extremely important for maintaining tissue integrity. Their roles include the immediate neutralisation of pathogens that have gained access to healthy tissue, the control of microbe-specific T cell responses and wound repair. Our studies focus on CXCL14, a “recent” chemokine with unknown receptor selectivity. Its broad expression in skin (and other epithelial tissues) together with its chemotactic function for monocytes suggest to us that CXCL14 may control an important aspect of monocyte-based immune surveillance.
Collectively, our peripheral tissue immune surveillance project emphasises an “under-researched” field in immunology with relevance for vaccination and skin disease.
As Engagement Lead and member of the Steering Group of the Systems Immunity Research Institute, Professor Matthias Eberl aims to reach out to all stake-holders and engage with patients, health care providers, schools, policy makers, media, funding bodies and industry. He has also set up a Lay Faculty of members of the public who help us reach our goals.