Lymphoid like stromal cells in a model of tertiary lymphoid organ formation

Nayar, Saba (2014). Lymphoid like stromal cells in a model of tertiary lymphoid organ formation. University of Birmingham. Ph.D.

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Abstract

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.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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