Figure 2.

Lineage relationships between lymphoid tissue inducer (LTi) cells and natural killer cell receptor-positive (NKR⁺) retinoic acid orphan receptor (ROR) γt⁺ innate lymphoid cells (ILCs). Two different models for the development of NKR⁺ RORγt⁺ ILCs have been proposed.^80,87 Model 1: LTi-like cells constitute an innate lymphocyte lineage defined by the expression of the orphan transcription factor RORγt. Genetic fate mapping for CD4 expression revealed that most NKR⁻ LTi-like cells are derived from a CD4⁺ progenitor.⁸⁰ Both CD4⁺ and CD4⁻ LTi-like cells up-regulate NKRs differentiating into CD4⁺ or CD4⁻ RORγt⁺ NKR-LTi cells. Dependent on the organ microenvironment NKR-LTi cells lose RORγt expression differentiating into RORγt⁻ NKR-LTi cells that are functionally distinct from RORγt⁺ NKR-LTi cells.⁸⁰ Model 2: The population of NKR⁻ RORγt⁺ ILCs contains two distinct innate lymphocyte lineages that can be discriminated by their levels of c-kit expression. The LTi cell lineage (CD4⁺ or CD4⁻) is characterized by a c-kit^high phenotype whereas the CD4^–, committed precursor to CD4⁻ NKR⁺ RORγt⁺ ILCs is c-kit^low.⁸⁷