Identifying innate signals initiating and perpetuating chronic inflammation
Chronic inflammatory disorders, especially rheumatic diseases, are triggered and maintained by effector mediators produced by the adaptive immune system, such as T cell and B cells. In T cells, inflammatory programs are induced by the T cell receptor (TCR) in conjunction with distinct cytokines and/or environmental signals. Recently, it appeared evident that emerging innate cell subsets lacking the TCR and collectively known as innate lymphoid cells (ILCs), exhibit a similar heterogeneity of effector modules, which can be activated in the course of inflammation. The signals and innate receptors instructing the different effector programs and their execution in ILCs remain largely unknown. Such innate sensors could also enhance effector functions in T cells, thus promoting inflammation in a TCR-independent fashion. Therefore, our main research focus is devoted to study the innate modules and triggers employed by ILCs and T cells to initiate and maintain inflammation in a TCR-independent fashion and to understand whether distinct inflammatory programs can be imprinted in ILCs to promote rheumatic diseases.
Recently, we have described a specific recognition strategy by Natural Killer (NK) cells which, in the absence of rearranged receptors, can detect mutated peptides derived from virus and host. Specific peptide recognition drives activation and expansion of a specialized subset of adaptive NK cells and contributes to determine their imprinting of pro-inflammatory cytokines, such as IFN-g expression (Hammer et al, Nature Immunology 2018). This data have important implications for our understanding of non-self and self-recognition by lymphocytes and how its dysregulation can lead to loss of tolerance and autoimmunity.
Such innate activating receptors may regulate not only ILC- but also T cell-mediated responses, as in the case of NKG2D. We have recently shown that this innate danger sensor is up-regulated in effector Th1 and pathogenic Th1+Th17 in vivo during arthritis model and its deletion in T cells can significantly ameliorate disease severity (Babic et al, under revision in JEM). This data identifies NKG2D as a potential check point and therapeutic target of T cell-mediated inflammatory diseases.
Altogether, the identification of the innate triggers and the specific signals driving the acquisition and the stable imprinting of distinct inflammatory programs in ILCs and T cells will be important to develop potentially new targets for the amelioration of chronic inflammation in rheumatic diseases.
Innate lymphoid cells
Prof. Chiara Romagnani, MD, Phd
Kerstin Juelke, Marina Babic
Christina Stehle, Quirin Hammer, Timo Rückert, Daniela Hernandez, Nils Müller
- Bluethgen N, Medical Systems Biology, Charité Universitätsmedizin, Berlin, Germany
- Cerwenka A, German Cancer Research Center (DKFZ), Innate Immunity , Heidelberg, Germany
- Malmberg KJ, Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
- Schüler T, Institute of Molecular and Clinical Immunology, Medical Faculty, Otto von Guericke University, Magdeburg, Germany
- Vivier E, Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, Marseille, France
- Walter J, Genetics/Epigenetics, University of Saarland, Saarbrücken, Germany
- Sawitzki B, Charité Medical University, Berlin
- Messerle M, Hannover Medical University
- Stölzel – HNO-Klinik, Charité Universitätsmedizin Berlin
The ILC World Revisited. Diefenbach A, Colonna M, Romagnani C. Immunity. 2017 Mar 21;46(3):327-332.
Hammer Q, Romagnani C. About Training and Memory: NK-Cell Adaptation to Viral Infections. Adv Immunol. 2017;133:171-207.
Hammer Q, Rückert T, Borst EM, Dunst J, Haubner A, Durek P, Heinrich F, Gasparoni G, Babic M, Tomic A, Pietra G, Nienen M, Blau IW, Hofmann J, Na IK, Prinz I, Koenecke C, Hemmati P, Babel N, Arnold R, Walter J, Thurley K, Mashreghi MF, Messerle M, Romagnani C. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Nat Immunol. 2018 May;19(5):453-463.
Cossarizza A, Chang HD, Radbruch A, … Romagnani C, et al. Guidelines for the use of flow cytometry and cell sorting in immunological studies. Eur J Immunol. 2017 Oct;47(10):1584-1797.
Hammer Q, Romagnani C. OMIP-039: Detection and analysis of human adaptive NKG2C+ natural killer cells. Cytometry A. 2017 Oct;91(10):997-1000.
Stehle C, Hernández DC, Romagnani C. Innate lymphoid cells in lung infection and immunity. Immunol Rev. 2018 Nov;286(1):102-119.
Hammer Q, Rückert T, Romagnani C. Natural killer cell specificity for viral infections. Nat Immunol. 2018 Aug;19(8):800-808.
Babic M, Romagnani C. Boosting Type 2 Immunity: When OX40L Comes from ILC2s. Immunity. 2018 Mar 21;46(3):327-332.
Babic M, Romagnani C. The Role of Natural Killer Group 2, Member D in Chronic Inflammation and Autoimmunity. Front Immunol. 2018 May 30;9:1219.