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Interaktionen von adaptiven und innaten Lymphozyten - Mechanismen, Funktionen und Konsequenzen

Fachliche Zuordnung Immunologie
Förderung Förderung von 2014 bis 2022
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 259808978
 
Erstellungsjahr 2022

Zusammenfassung der Projektergebnisse

Local networks of tissue-resident lymphocytes are strategically positioned in most anatomical compartments, including epithelial barrier surfaces such as the skin, the lung and the gut, where they provide immune surveillance and front-line defense to microbial invasion. In addition to immediate immunological effector activities, tissue-resident lymphocytes interact with both hematopoietic and non-hematopoietic cells and contribute to physiologic mechanisms of tissue homeostasis, repair and barrier function. Under physiologic conditions, the size, microanatomical localization and subset composition of the local pools of lymphocytes differs quite dramatically among different organs, but the mechanisms that instruct cell-intrinsic adaptations and the development, maintenance and coordinated function of resident lymphocytes in specific tissue environments are poorly understood. During the time of the Emmy Noether program, we have investigated the differentiation and heterogeneity of recently discovered innate lymphoid cells (ILCs) and tissue-resident memory T cells, and their potential interactions with cellular players of the adaptive immune system. Our work established that ILCs are tissue-resident cells, raising the question of how these cells can locally differentiate and self-renew. Addressing this question, we identified multipotent tissue-resident ILC progenitors that can locally mature and generate organ-specific ILCs. We could further show that diverse skin-resident ILCs can locally differentiate from a naïve-like population and acquire pathogenic effector states that contribute to experimental psoriasis. We then asked how ILC1s, known to exhibit pronounced tissue-specific phenotypes and functions, acquire effector function, and how tissue-specific ILC heterogeneity, population structure and subset specialization is established, and how these processes are transcriptionally regulated. We identified Tcf1hi ILC1s characterized by a “stem-like” expansion potential. These cells, that we identified across tissues, diversify into downstream effectors while losing expansion potential and gaining expression of effector molecules that enable cytotoxic function. Our findings provide a novel conceptual framework that connects tissuespecific phenotypes of ILC1s along a uniform differentiation pathway driven by the transcription factor Hobit. In addition, we have contributed to the identification of a novel ILC1-like NK cell population in the spleen, bridging innate and adaptive antiviral immunity. We further investigated interactions of ILCs and NK cells with T cells in several infection models, and identified the IL-2 and CD25- dependent regulation of antiviral T cells by ILC1 in the liver. We investigated the potential relevance of these molecules for ILC and NK cell biology in a broad range of experimental disease models. Tracking the generation of tissue-resident memory T cells in response to local infection, we could show that these cells compete for antigenic stimulation in the infected tissue, highlighting the tissue-intrinsic differentiation of resident lymphocytes, and revealing a mechanism for the “selection” of an optimal T cell repertoire into limited tissue-niches. Together, our work has contributed major insights into the development, functions and interactions of tissue-resident innate and adaptive lymphocytes, and their regulation during ontogeny, infection and inflammatory disease.

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