Ectopic Lymphoid Structures – reducing the spatio-temporal unit to provide effective local immunity by TRM in non-lymphoid tissues?

≪p≫Effective tissue immunity requires immune cell surveillance, which is mediated by antigen recognition and T cell responses. The concept of tissue-resident T cells was introduced more than 10 years ago, describing a highly specialized memory T cell population (TRM) with the unique feature to reside in non-lymphoid tissues (NLTs), providing an effective first line adaptive immune response against established pathogens. Immune surveillance of NLTs requires the orchestration of various tissue-resident and non-resident immune cells, as well as a high degree of cellular migration within tissues to provide an effective and timely response to antigen encounter, which is performed by antigen-specific TRM. By revealing the heterogeneity of intrahepatic T cells within the first single-cell atlas of human T cells isolated from human inflamed livers, we recently discovered a population of liver-resident naive-like CD4+ T cells with the potential to acquire a TH17 polarization state. However, in the mammalian liver, the gatekeeper of immune tolerance to alimentary and commensal derived macromolecules, the role of TRM has not yet been fully understood. Furthermore, it is unclear to what extent they are involved in providing a proper immunity to the host, or whether they can also contribute to immune pathology. In the context of chronic inflammation or cancer, NLTs establish ectopic lymphoid structures (ELS), which are associated with favorable outcome in cancer but with disease progression of autoimmunity. ELS are heterogeneous and can consist of a small cluster of lymphoid cells, or even form organized lymphoid follicles with the structural features of lymph nodes. How ELS are composed in the liver, and which role they play in mediating tissue-specific immunity remains unclear. We hypothesize, that ELS functionally reduce the spatio-temporal unit to improve effective tissue immunity by TRM cells. To test this hypothesis, we aim to characterize the cellular network within liver ELS and understand the role of ELS in the reactivation and local immune response of TRM in the liver.We will test our hypothesis by using cutting edge imaging methods including spatial transcriptomics, multiplex immunofluorescence and 2 photon laser microscopy in mice from specific husbandry conditions and using an infection model. Our results will add to the understanding of tissue specific immunity and ELS function in the liver. By doing so we will decipher ELS function, which will build the basis for immunomodulatory therapies in the future.≪/p≫