Notch, Id2, and RORγt sequentially orchestrate the fetal development of lymphoid tissue inducer cells

Lymphoid tissue development is initiated during embryogenesis by the migration of lymphoid tissue inducer (LTi) cells from the fetal liver to the periphery, where they induce the formation of lymph nodes and Peyer's patches. In the fetal liver, a subset of common lymphoid progenitors (CLPs) that expresses the integrin alpha 4 beta 7 gives rise to LTi cells, a process strictly dependent on the expression of the transcriptional repressor Id2 and the nuclear hormone receptor retinoic acid-related orphan receptor gamma t (ROR gamma t). In this study, we show that Id2 and ROR gamma t are sequentially up-regulated during LTi cell development, matching two waves of differentiation with opposite requirements for Notch signaling. Both the expression of Id2 and Notch are required for the generation of alpha 4 beta 7(+) ROR gamma t(-) fetal progenitors, but Notch subsequently blocks progression to the ROR gamma t(+) stage and final maturation of LTi cells. Notch is therefore a necessary switch to engage the LTi developmental pathway, but needs to be turned off later to avoid diversion to the T cell fate.