NKT cells represent a small subset of glycolipid-recognizing T cells that are heavily implicated in human allergic, autoimmune, and malignant diseases. In the thymus, precursor cells recognize self-glycolipids by virtue of their semi-invariant TCR, which triggers NKT cell lineage commitment and maturation. During their development, NKT cells are polarized into the NKT1, NKT2, and NKT17 subsets, defined through their cytokine-secretion patterns and the expression of key transcription factors. However, we have largely ignored how the differentiation into the NKT cell subsets is regulated. In this article, we describe the mRNA-binding Roquin-1 and -2 proteins as central regulators of murine NKT cell fate decisions. In the thymus, T cell–specific ablation of the Roquin paralogs leads to a dramatic expansion of NKT17 cells, whereas peripheral mature NKT cells are essentially absent. Roquin-1/2–deficient NKT17 cells show exaggerated lineage-specific expression of nearly all NKT17-defining proteins tested. We show through mixed bone marrow chimera experiments that NKT17 polarization is mediated through cell-intrinsic mechanisms early during NKT cell development. In contrast, the loss of peripheral NKT cells is due to cell-extrinsic factors. Surprisingly, Roquin paralog–deficient NKT cells are, in striking contrast to conventional T cells, compromised in their ability to secrete cytokines. Altogether, we show that Roquin paralogs regulate the development and function of NKT cell subsets in the thymus and periphery.
This work was supported by the Deutsche Forschungsgemeinschaft through Grants SCHM2440-3 and SFB 1054 A02 (to M.S.-S.). J.C.V. and K.D.H. received Ph.D. stipends from the Ernst Schering Foundation and the Boehringer Ingelheim Fonds, respectively.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- 7-aminoactinomycin D
- median fluorescence intensity
- mesenteric lymph node
- mechanistic target of rapamycin
- peripheral lymph node
- promyelocytic leukemia zinc finger
- signaling lymphocyte activation molecule
- follicular Th
- Th poxviruses and zinc finger and Krüppel family
- tuberous sclerosis 1.
- Received October 6, 2016.
- Accepted January 18, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.