Tertiary lymphoid organs (TLOs) are a hallmark of many chronic immune-mediated inflammatory diseases. However, till date the series of events leading to stromal cell activation in TLOs and their role in the inflammatory process remain unclear.
Using a model of inducible TLO formation in the salivary glands of mice we explored the role of gp38+LTβR+ lymphoid-like stromal cells (LLSc) during TLO development and show that they acquire the capability to produce lymphoid chemokines (CKs)/cytokine and drive lymphocyte compartmentalization. In this thesis, we provide evidence that stromal cell activation is a multi-step process with three distinct phases mediated by three major cytokines (IL-13, IL-22 and LTβ).
We demonstrate that during TLO formation, IL-4Rα engagement via IL-13 on quiescent tissue-resident fibroblasts induces the phenotypic acquisition of lymphoid features by LLSc. IL22 then initiates the proliferation and expansion of the LLSc population, required for the expression of lymphoid CKs/cytokines and ANA autoantibody production. Finally, we show that LTβR ligation is necessary for the establishment of a fully mature TLO structure once IL-22 driven LLSc proliferation has occurred. Based on our findings we have identified three different phases of stromal cell activation in TLOs which are all potentially targets of future therapy
