Medical Biology - Theses
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ItemDistinct requirements for T-bet and Nfil3 for the generation of innate lymphoid cell populations( 2014)Innate lymphoid cells (ILCs) are key effector cells found at mucosal surfaces. They are crucial for lymphoid tissue development and preserving the delicate balance of tolerance, immunity and inflammation. ILCs are grouped into three distinct lineages namely ILC1, ILC2 and ILC3 based on their cytokine and transcription factor expression profiles. The lineage specification, development and function of ILCs depend on the timely expression of a precise set of transcription factors that regulate distinct checkpoints during their development and maturation. The full array of molecular networks that are responsible for generating ILC diversity is, however, yet to be fully characterized and is the focus of this thesis. Firstly, the role of the T helper 1 lineage specifying transcription factor T-bet (encoded by Tbx21) in regulating the diversity of ILC3 populations was investigated. Here T-bet was found to be the essential regulator of the NKp46 expressing population of ILC3 termed NCR+ ILC3. T-bet was necessary for the transition from NCR- ILC3 precursors into NCR+ ILC3s. Furthermore, expression of T-bet was intricately regulated by the Notch signaling pathway. T-bet regulated the expression of a precise set of molecules unique to NCR+ ILC3. Loss of T-bet also resulted in reduced protection against the intestinal pathogen Citrobacter rodentium (C. rodentium) which correlated with reduced IL-22 produced from ILC3. This pathology seen in T-bet deficient mice, however, was not solely due to loss of NCR+ ILC3. Mice specifically deficient in NCR+ ILC3 were able to broadly control C. rodentium to infection, although mild pathologies were evident. Secondly, the transcription factor Nfil3 is implicated in a number of immune cell lineages including natural killer (NK) cell development. This thesis further demonstrates that all ILC populations display high Nfil3 expression and genetic ablation of Nfil3 results in a global reduction of all ILC lineages including ILC precursors. Furthermore, loss of Nfil3 selectively disrupted Peyer’s patch but not lymph node formation. Loss of Nfil3 consequently resulted in reduced protection to Citrobacter rodentium infection. Therefore, T-bet and Nfil3 exquisitely control the diversity of not only the adaptive but also the innate immune system to confer protection against multiple pathogenic organisms that infect through barrier surfaces.