The zinc-finger transcription factor MAZR regulates iNKT cell subset differentiation

Maria Jonah Orola,Caroline Tizian,Tatjana Stojakovic,Ursula Wiedermann,Alexandra Franziska Gülich,Shinya Sakaguchi,Ci Zhu,Marlis Alteneder,Wilfried Ellmeier,Liisa Andersen,Michael Trauner

doi:10.1007/s00018-019-03119-z

Abstract

Invariant natural killer T (iNKT) cells represent a subgroup of innate-like T cells and play an important role in immune responses against certain pathogens. In addition, they have been linked to autoimmunity and antitumor immunity. iNKT cells consist of several subsets with distinct functions; however, the transcriptional networks controlling iNKT subset differentiation are still not fully characterized. Myc-associated zinc-finger-related factor (MAZR, also known as PATZ1) is an essential transcription factor for CD8+ lineage differentiation of conventional T cells. Here, we show that MAZR plays an important role in iNKT cells. T-cell lineage-specific deletion of MAZR resulted in an iNKT cell-intrinsic defect that led to an increase in iNKT2 cell numbers, concurrent with a reduction in iNKT1 and iNKT17 cells. Consistent with the alteration in the subset distribution, deletion of MAZR also resulted in an increase in the percentage of IL-4-producing cells. Moreover, MAZR-deficient iNKT cells displayed an enhanced expression of Erg2 and ThPOK, key factors for iNKT cell generation and subset differentiation, indicating that MAZR controls iNKT cell development through fine-tuning of their expression levels. Taken together, our study identified MAZR as an essential transcription factor regulating iNKT cell subset differentiation and effector function.

Highlights

Invariant natural killer T cells are a small subgroup of T cells expressing semi-invariant T-cell receptors (TCRs), which consist of an invariant α chain and a limited repertoire of β chains [1, 2]
The percentages of thymic stage 2 (CD24−CD44+NK1.1–) Invariant natural killer T (iNKT) cells were significantly increased in Myc-associated zinc-finger-related factor (MAZR)-cKOLck/GFP mice compared to W TLck/GFP mice, along with a corresponding reduction in the percentage of stage 3 (CD24−CD44+NK1.1+) iNKT cells (Fig. 1c, d)
We investigated the role of the transcription factor MAZR in the development and effector function of iNKT cells

Summary

Introduction

Invariant natural killer T (iNKT) cells are a small subgroup of T cells expressing semi-invariant T-cell receptors (TCRs), which consist of an invariant α chain and a limited repertoire of β chains [1, 2]. They recognize lipid antigens such as alpha-galactosylceramide (α-GalCer) presented by CD1d, a non-classical MHC class I molecule, and are capable of rapidly producing a large amount of cytokines upon activation [3, 4]. INKT cell precursors start to express the transcription factor early growth response protein 2 (Egr2) at a high level [7]. Key transcription factors controlling iNKT cell development have been identified [5, 14, 17], the fine-tuning of iNKT subset differentiation is not fully understood

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Conclusion