Most anatomical compartments, including mucosal barrier surfaces, solid organs and vascular spaces host different types of tissue-resident lymphocytes providing local networks for immune surveillance and front-line defense to microbial invasion. In addition to immediate effector functions, tissue-resident lymphocytes orchestrate and regulate inflammatory responses, and contribute to tissue homeostasis, repair and barrier function. Understanding the generation and function of tissue-resident lymphocytes is therefore expected to reveal targets for improving vaccination and immunotherapy. Barrier tissues of free-living mice and men, but not those of laboratory mice kept under specific pathogen free conditions, are continuously exposed to an array of antigenically complex pathogens, microbial symbionts and environmental factors, which dramatically alter the abundance, composition and basal activation state of local pools of tissue-resident cells. Therefore, we proposed to study the development, functions and cellular interactions of tissue-resident lymphocytes in experimental models that mirror “real-life” contexts.
The project had three major aims: first, to study the mechanisms of generation and effector differentiation of tissue-resident lymphocytes, second, to study the biology of tissue-resident memory T cells in “real-life contexts” (restore physiologic microbial exposure in SPF mice), and third, to investigate if and how localized infections and vaccinations can induce tissue-resident NK cells and ILC1.
We identified Tcf1hi stem-like ILC1s, that are present across tissues and locally give rise to tissue-resident effector lymphocytes. Tcf1hi stem-like ILC1s 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 tissue-specific phenotypes of ILC1s along a uniform differentiation pathway driven by the transcription factor Hobit.
We established models of sequential infections that mimic the quasi-physiologic encounter of pathogens of humans and free-living animals during live. The exposure to these frequent pathogens is a major “educating” factor of the immune system, and influences numbers and phenotypes of tissue-resident lymphocytes. We are using these experimental models to study ILC, NK and TRM cell differentiation in more physiologic disease contexts. We have mapped long-term changes in cellular composition of tissues induced by pathogen encounter and could show increased resilience to viral infection. The established experimental models have gained attraction from other scientists and have stimulated new studies in the context of diseases that are highly relevant to our society, e.g. myocardial infarction, cancer and obesity.
In our efforts to understand how infection history shapes tissue-niches of resident lymphocytes, we found that circulating NK cells are recruited and can differentiate into tissue-resident memory-like cells upon viral and bacterial infection of skin. We have dissected the developmental paths and transcriptional requirements of these cells, and demonstrate their capacity to mediate accelerated effector responses during reinfection. Our findings highlight that the “repertoire” of innate lymphocytes populating tissues can be adapted in response to infection, through mechanisms that are distinct from currently known developmental paths of NK cells and ILC1 seeding tissues during ontogeny. Our analyses suggest intriguing similarity of the newly identified tissue-resident NK cells with CD56brightTCF1hi NK cells in human tissues. Our work identifies novel tissue-resident lymphocyte populations in response to local skin infection, and identifies molecular targets that will be tested in future research for improving vaccination approaches and cellular therapies.
In conclusion, our work has identified novel cellular and molecular pathways that regulate the differentiation and effector function of tissue-resident lymphocytes. We expect that these novel insights will help to improve vaccination approaches and cellular therapies.
