Re-evaluating the origins group 2 innate lymphoid cells through the lens of T-cell development

The discovery of innate lymphoid cells (ILCs) has revolutionized our understanding of innate immunity and immune cell interactions at epithelial barrier sites. Their presence and maintenance are critical for modulating immune homeostasis, responding to injury or infection, and repairing damaged tissues. ILCs are remarkably similar to CD4+ T helper subsets in terms of function and transcription factors required for their development but are distinguished by their lack of antigen specific receptors. Despite their similarities, the absence of a surface TCR and presence of ILCs/precursors in adult bone marrow has led to speculation that ILCs and T cells develop separately from lineages that branch at the point of precursors within the bone marrow. Considering the common lineage markers and effector cytokine profiles shared between ILCs and T cells, it is surprising that the status of the TCR loci in ILCs was not fully explored at the time of their discovery. In this thesis, we demonstrate that a high proportion of peripheral tissue ILC2s have TCRγ chain gene rearrangements and TCRδ locus deletions. Detailed analyses of these loci show abundant frameshifts and premature stop codons that would encode non- functional TCR proteins. Collectively, these data argue that ILC2 can develop from T cells that fail to appropriately rearrange TCR genes, potentially within the thymus.Medicine, Faculty ofExperimental Medicine, Division ofGraduat