Sustained innate interferon is an essential inducer of tertiary lymphoid structures

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)alpha in lymphoid cells, which stimulate stromal cells to produce the B-cell-attracting chemokine CXCL13 through LT beta R-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 LT beta R. 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. Calvanese et al. discovered that type I interferon is an essential upstream mediator for the development of tertiary lymphoid structures in the lungs. IFNAR1 signaling results in the production of LT alpha, which in turn induces the B-cell attractant CXCL13. Further, IFNAR1-signaling induces T-cell-attracting chemokines independently of LT beta R-signaling. image