The Transcription Factor PLZF Directs the Effector Program of the NKT Cell Lineage

Abstract

Summary The transcriptional control of CD1d-restricted NKT cell development has remained elusive. We report that PLZF (promyelocytic leukemia zinc finger; Zbtb16), a member of the BTB/POZ-ZF family of transcription factors which includes the CD4 lineage-specific c-Krox (Th-POK, Zbtb7b), is exquisitely specific to CD1d-restricted NKT cells and human MR1-specific MAIT cells. PLZF was induced immediately after positive selection of NKT cell precursors and PLZF-deficient NKT cells failed to undergo the intrathymic expansion and effector differentiation that characterize their lineage. Instead, they preserved a naïve phenotype and were directed to lymph nodes. Conversely, transgenic expression of PLZF induced CD4 thymocytes to acquire effector differentiation and migrate to non-lymphoid tissues. We suggest that PLZF is a transcriptional signature of NKT cells that directs their innate-like effector differentiation during thymic development.

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

“…BCL6 is expressed at high levels in germinal center B cells 9 and T follicular helper cells 10 that together control the germinal center response. Promyelocytic leukemia zinc finger (ZBTB16) is required for natural killer T-cell development 11 and expression of promyelocytic leukemia zinc finger has recently been shown to identify a multipotent progenitor of innate lymphoid cells. 12 T H -inducing POZ/Kruppel-Like factor (ThPOK, ZBTB7B) is a master regulator of T H -cell development in the thymus.…”

Expression of the promyelocytic leukemia zinc-finger in T-lymphoblastic lymphoma and leukemia has strong implications for their cellular origin and greater association with initial bone marrow involvement

“…2,3,7,9,11 Recently, an intriguing role of PLZF in immune system has been described. 16,17 Innate T cells bridges the innate and adaptive immune systems, including gdT cells and several subsets of abT cells. In general, innate T cells (of an ab T-cell lineage) develop in the thymus from double-positive progenitors.…”

“…27 PLZF is essential for the development of invariant NKT cells with acquisition of their unique innate-like properties in a mouse system. 16,17 Recently, our group and others have reported a new distinct subset of innate abT cells (T-T CD4 T cells), which are selected by MHC class II-expressing thymocytes and also depend on PLZF for their development. [28][29][30] Moreover, we reported that the generation of T-T CD4 T cells is a physiological process in humans.…”

“…16,17 In humans, the number of PLZF ( þ ) thymocytes is high during the fetal stage and decreases in the postnatal period. 18 In a mouse system where all CD4 T cells were designed to express PLZF molecule, PLZF was detected in a portion of T-T CD4 T cells.…”

“…1,[12][13][14][15] It was recently found that PLZF is essential for the development of natural killer T (NKT) cells and acquisition of the unique innate-like characteristics of innate T cells. [16][17][18][19] Innate immunity is mediated by natural killer (NK) cells, monocytes/macrophages, and granulocytes. In general, this pathway enables the recognition of pathogens via germlineencoded pattern-recognition receptors (eg, the Toll-like receptor) and activation of the immediate immune response, and it does not involve immunological memory.…”