PLZF drives the innate-like effector program of NKT cells

Abstract

Lineage fate decisions in hematopoietic development have been shown to rely on the activity of signature transcription factors such as Th-POK, T-bet, Foxp3, and others. These factors are often characterized by highly specific expression and the ability to confer lineage characteristics upon ectopic expression. Natural Killer T (NKT) cells are an innate-like T cell subset for which there has long been suspected the existence of a lineage-determining factor. However, significant effort thus far has only revealed factors with known roles in conventional T cell lineages. For example, RelB and T-bet have been shown to be critical for terminal maturation and acquisition of the NK program, both late stage events. Utilizing genome-wide expression analysis to search for unique transcription factors in NKT cells, we identified PLZF (Zbtb16) for unique and strong expression compared to conventional T cell populations. Cousin to other hematopoietic lineage determinants such as Bcl6 and Th-POK (Zbtb7b), PLZF was necessary for the development and effector phenotype of NKT cells. Interestingly, other innate-like T cell lineages such as MAIT cells and Vγ1Vδ6.3 T cells also express PLZF and, at least in the case of the latter, rely on it for their innate-like effector program. Ectopic expression of PLZF in conventional CD4 T cells conferred NKT cell characteristics including altered tissue trafficking and dual IL-4/IFNγ production, indicating that PLZF is indeed a lineage-specifying factor. This conversion is independent of TCR specificity and clonal expansion, suggesting that PLZF could be used for cell-based therapies. Therefore, PLZF specifies the lineage characteristics of innate-like T cells and bestows upon them properties inaccessible to mainstream CD4 and CD8 T cell populations.