ABSTRACT
Tertiary lymphoid structures (TLS) resemble follicles of secondary lymphoid organs and develop in nonlymphoid tissues during inflammation and cancer. Which cell types and signals drive the development of TLS is largely unknown. To investigate early events of TLS development in the lungs, we repeatedly instilled p(I:C) plus ovalbumin (Ova) intranasally. This induced TLS ranging from lymphocytic aggregates to organized and functional structures containing germinal centers. We found that TLS development is independent of FAP+ fibroblasts, alveolar macrophages, or CCL19 but crucially depends on type I interferon (IFN-I). Mechanistically, IFN-I initiates two synergistic pathways that culminate in the development of TLS. On the one hand, IFN-I induces lymphotoxin (LT)α in lymphoid cells, which stimulate stromal cells to produce the B-cell-attracting chemokine CXCL13 through LTßR-signaling. On the other hand, IFN-I is sensed by stromal cells that produce the T-cell-attracting chemokines CXCL9, CXCL10 as well as CCL19 and CCL21 independently of LTßR. Consequently, B-cell aggregates develop within a week, whereas follicular dendritic cells and germinal centers appear after 3 weeks. Thus, sustained production of IFN-I together with an antigen is essential for the induction of functional TLS in the lungs.
Subject(s)
Immunity, Innate , Interferon Type I , Tertiary Lymphoid Structures , Animals , Tertiary Lymphoid Structures/immunology , Mice , Interferon Type I/metabolism , Interferon Type I/immunology , Immunity, Innate/drug effects , Chemokine CCL19/metabolism , Lung/immunology , Chemokine CCL21/metabolism , Chemokine CXCL13/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/drug effects , Lymphotoxin beta Receptor/metabolism , Lymphotoxin beta Receptor/immunology , Mice, Inbred C57BL , Stromal Cells/immunology , Stromal Cells/drug effects , Stromal Cells/metabolism , Lymphotoxin-alpha/metabolism , Lymphotoxin-alpha/immunology , Germinal Center/immunology , Ovalbumin/immunology , Ovalbumin/administration & dosage , Signal Transduction/immunology , Signal Transduction/drug effects , Fibroblasts/immunology , Fibroblasts/drug effects , Macrophages, Alveolar/immunology , Macrophages, Alveolar/drug effects , Chemokine CXCL10/metabolism , Chemokine CXCL10/immunology , Mice, Knockout , Chemokine CXCL9/metabolismABSTRACT
The liver is a major metastatic target organ, and little is known about the role of immunity in controlling hepatic metastases. Here, we discovered that the concerted and nonredundant action of two innate lymphocyte subpopulations, conventional natural killer cells (cNKs) and tissue-resident type I innate lymphoid cells (trILC1s), is essential for antimetastatic defense. Using different preclinical models for liver metastasis, we found that trILC1 controls metastatic seeding, whereas cNKs restrain outgrowth. Whereas the killing capacity of trILC1s was not affected by the metastatic microenvironment, the phenotype and function of cNK cells were affected in a cancer type-specific fashion. Thus, individual cancer cell lines orchestrate the emergence of unique cNK subsets, which respond differently to tumor-derived factors. Our findings will contribute to the development of therapies for liver metastasis involving hepatic innate cells.