Enforced expression of the Ikaros isoform IK5 decreases the numbers of extrathymic intraepithelial lymphocytes and natural killer 1.1+ T cells.

The zinc-finger protein Ikaros plays an important role in lymphoid homeostasis, and loss of Ikaros expression through germline disruption impairs lymphoid development. However, the role played by Ikaros after commitment to the T-cell lineage is unclear. To address this question, this study used the lck proximal promoter to drive the expression in T-cell progenitors of a naturally occurring short Ikaros isoform (IK5), which lacks the DNA-binding domain, reasoning that IK5 will form heterodimers with long isoforms and perturb their function. The IK5 transgene led to a selective and dramatic decrease in extrathymic intestinal intraepithelial lymphocytes (IELs) and natural killer 1.1+ T (NK T) cells with little effect on conventional alphabeta T cells, which resembles the T-cell phenotype of interleukin-15 receptor alpha chain (IL-15Ralpha) and IL-2/IL-15 receptor beta chain (IL-2Rbeta) knockout mice. The expression of IL-2Rbeta on double-negative T-cell progenitors of bi-5 was reduced, but enforced expression of IL-2Rbeta did not rescue IELs or NK T cells in bi-5 transgenic mice, suggesting that Ikaros or Ikaros family members regulate the expression of additional genes that are essential for the development of IELs and NK T cells. The study concludes that modest changes in the ratio of short to long Ikaros isoforms can substantially perturb T-cell development, and the development of IELs and NK T cells is particularly sensitive to such changes.