transcriptional regulator PLZF induces the development of CD44 high memory phenotype T cells

Transcriptional pathways controlling the development of CD44hi memory phenotype (MP) T cells with "innate-like" functions are not well understood. Here we show that the BTB (bric-a-brac, tramtrack, broad complex) domain-containing protein promyelocytic leukemia zinc finger (PLZF) is expressed in CD44hi, but not in CD44lo, CD4⁺ T cells. Transgenic expression of PLZF during T cell development and in CD4⁺ and CD8⁺ T cells induced a T cell intrinsic program leading to an increase in peripheral CD44hi MP CD4⁺ and CD8⁺ T cells and a corresponding decrease of naïve CD44lo T cells. The MP CD4⁺ and CD8⁺ T cells produced IFNγ upon PMA/ionomycin stimulation, thus showing innate-like function. Changes in the naïve versus memory-like subset distribution were already evident in single-positive thymocytes, indicating PLZF-induced T cell developmental alterations. In addition, CD1d-restricted natural killer T cells in PLZF transgenic mice showed impaired development and were severely reduced in the periphery. Finally, after anti-CD3/CD28 stimulation, CD4⁺ transgenic T cells showed reduced IL-2 and IFNγ production but increased IL-4 secretion as a result of enhanced IL-4 production of the CD44hiCD62L⁺ subset. Our data indicate that PLZF is a novel regulator of the development of CD44hi MP T cells with a characteristic partial innate-like phenotype.