The Role of T-box Transcription Factors in the Development and Plasticity of Natural Killer Cell Lineages

Type 1 innate lymphocytes comprise two developmentally divergent lineages, type 1 helper innate lymphoid cells (hILC1s) and conventional NK (cNK) cells. All type 1 innate lymphocytes (ILCs) express the transcription factor T-bet, but cNK cells additionally express Eomesodermin (Eomes). We show that deletion of Eomes alleles at the onset of type 1 ILC maturation using NKp46-Cre imposes a substantial block in cNK cell development. Formation of the entire lymphoid and non-lymphoid type 1 ILC compartment appears to require the semi-redundant action of both T-bet and Eomes. To determine if Eomes is sufficient to redirect hILC1 development to a cNK cell fate, we generated transgenic mice that express Eomes when and where T-bet is expressed using Tbx21 locus control to drive expression of Eomes codons. Ectopic Eomes expression induces cNK cell-like properties across the lymphoid and non-lymphoid type 1 ILC compartments. To investigate if T-bet is sufficient to direct type 1 ILC development into the hILC1 lineage, we also generated transgenic mice in which Tbx21 locus control drives expression of T-bet codons. Enforced T-bet expression, however, does not appear sufficient to induce hILC1-like attributes among type 1 ILCs. Subsequent to their divergent lineage specification, hILC1s and cNK cells possess substantial developmental plasticity elicited by the absence or presence of Eomes.