Essential role of Mediator subunit Med1 in invariant natural killer T-cell development

Abstract

CD1d-restricted invariant NKT (iNKT) cells are a unique lineage of T lymphocytes that regulate both innate and adaptive immunity. The Mediator complex forms the bridge between transcriptional activators and the general transcription machinery. Med1/ TRAP220 (also called DRIP205) is a key component of Mediator that interacts with ligand-bound hormone receptors, such as the vitamin D receptor. Here, we show that T-cell-specific Med1 deficiency results in a specific block in iNKT cell development but the development of conventional αβ T cells remains grossly normal. The defect is cell-intrinsic and depends neither on apoptosis, cellcycle control, nor on CD1d expression of CD4 + CD8 + double-positive thymocytes. Surprisingly, ectopic expression of a Vα14-Jα18 T-cell receptor transgene completely rescues the defect caused by Med1 deficiency. At the molecular level, thymic iNKT cells in Med1animals display reduced levels of IL-2Rβ and T-bet expression and could not complete terminal maturation. Thus, Med1 is essential for a complete intrathymic development of iNKT cells.

Impaired Autophagy, Defective T Cell Homeostasis, and a Wasting Syndrome in Mice with a T Cell–Specific Deletion of Vps34

“…The positively selected iNKT cells then arise from the DP stage to mostly become CD4 + iNKT cells and a smaller population of CD4 − CD8 − iNKT cells (39, 40). iNKT cell development progresses through various stages, based on their early expression of CD24 and CD44 and late expression of NK1.1 (41–43). After their development, these cells populate peripheral lymphoid organs, mainly liver and spleen.…”

iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions

“…Signaling from the iV14TCR is crucial for early iNKT cell development (7)(8)(9)(10). iNKT cell terminal maturation from stages 2 to 3 requires signal from the IL-15 and vitamin D receptors as well as the transcription factor T-bet and mediator subunit Med1 (11)(12)(13)(14). How T-bet is regulated for iNKT terminal maturation is poorly understood.…”

Shared and distinct transcriptional programs underlie the hybrid nature of iNKT cells

“…For instance, NF-κB and Ras/MapK pathway members such as NFkb1, RelB , Ras/MapK and Egr2 were upregulated in both i NKT and non- i NKT thymocyte populations 4 (data not shown). Other genes known to affect i NKT cells ontogeny, Bcl11b 46 and the chromatin modifier Med1 47 for example, exhibited little or no transcriptional variation over the course of i NKT cell differentiation. The functional regulation of these and other genes not detected in our analyses may thus be controlled at post-transcriptional levels.…”