The transcription factor Th-POK negatively regulates Th17 differentiation in Vα14i NKT cells

The majority of mouse V alpha 14 invariant natural killer T (V alpha 14i NKT) cells produce several cytokines, including IFN gamma and IL-4, very rapidly after activation. A subset of these cells, known as NKT17 cells, however, differentiates in the thymus to preferentially produce IL-17. Here, we show that the transcription factor-known as T helper, Poxviruses, and Zinc-finger and Kruppel family, (Th-POK)-represses the formation of NKT17 cells. V alpha 14i NKT cells from Th-POK-mutant helper deficient (hd/hd) mice have increased transcripts of genes normally expressed by Th17 and NKT17 cells, and even heterozygosity for this mutation leads to dramatically increased numbers of V alpha 14i NKT cells that are poised to express IL-17, especially in the thymus and lymph nodes. In addition, using gene reporter mice, we demonstrate that NKT17 cells from wild-type mice express lower amounts of Th-POK than the majority population of V alpha 14i NKT cells. We also show that retroviral transduction of Th-POK represses the expression of the Th17 master regulator ROR gamma T in V alpha 14i NKT-cell lines. Our data suggest that NKT17-cell differentiation is intrinsically regulated by Th-POK activity, with only low levels of Th-POK permissive for the differentiation of NKT17 cells. (Blood.2012;120(23):4524-4532)