The BTB–zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions

Abstract

Invariant Natural Killer T cell (iNK Tcell) have an innate immunity-like rapidity of response and the capacity to modulate effector functions of other cells. We show that the BTB-ZF transcriptional regulator, PLZF, is specifically expressed in iNKT cells. iNKT cells develop in the absence of PLZF, but lack many innate T cell features. PLZF deficient iNKT cells accumulate in the lymph nodes rather than in the liver and do not have an activated phenotype or express NK markers. PLZF deficient iNKT cells do not secrete high levels of IL-4 and IFNγ upon activation, however some cells produce either IL-4 or IFNγ, but not both. PLZF, therefore, is an iNKT cell specific transcription factor that is necessary for full functionality.Nearly all hematopoietic cells mature in the bone marrow. In contrast, multipotent progenitor T cells leave the bone marrow and home to the thymus, where signals from stromal cells are required for commitment to the T lineage 1 . Once directed into the T lineage, the cells undergo a rigorous selection process that eliminates more than 95% of the candidate T cells. Full maturation requires the expression of a T cell receptor (TCR) that binds self-peptide:self-MHC complexes with sufficient avidity. At some point during development, T cells are directed into one of several distinct T cell lineages such as CD4 single positive "helper" cells, CD8 single positive "killer" cells or CD4 + CD25 + regulatory cells. Commitment to these various lineages defines the specialized functions of the cell, which is critical since each cell type plays an essential and distinct role for host defense. The genes responsible for directing multipotent T cell progenitors into the various lineages are largely unknown 2 .Correspondence and requests for materials should be addressed to D.B.S (Email: santangd@mskcc.org). NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAmong the various lineages of T cells, invariant Natural Killer T cells (iNKT cells) have several unique phenotypic traits such as the expression of receptors typically associated with Natural Killer cells (NK cells), the constitutive expression of activation markers and extremely restricted TCR diversity 3 . iNKT cells express an identical TCRα chain and most use a TCRβ chain that utilizes the Vβ8.2 gene segment. This TCR confers specificity to the non-MHC encoded self-molecule, CD1d, which binds and presents glycolipids rather than the typical peptide cargo presented by conventional MHC molecules.iNKT cells are also functionally distinct. Of particular interest is their ability to secrete large quantities of a variety of cytokines only minutes after activation via the TCR 3 . The rapid response of these cells, the conserved nature of the TCR and their indirect ability to modulate the function of many different cell types of the immune system has led to the appreciation that iNKT cells lay at a functional cusp between the innate and adaptive immune systems 4 . The broad range of cytokines released by iNKT cells results in th...

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.…”

Type I natural killer T cells: naturally born for fighting

“…The deficiency of E protein transcription factor HEB seriously blocked the development of NKT cells at the stage 0 but made no difference to conventional T cells because it failed to regulate thymocyte survival or distal rearrangements of the TCRα chain [34] . Promyelocytic leukemia zinc finger transcription factor (PLZF) is responsible for the early stages (stage 1 to 2) of NKT cell maturation and production of the functional cytokines, even in the absence of SLAM-SAP-Fyn signaling [35,36] . Recently, the identification of selective function for the transcription factor early growth response 2 (Egr2) in maturation and homeostasis of NKT cells also emphasizes the importance of the calcineurin-NFAT-Egr2 pathway in the development of NKT cells.…”