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Eomes Transcription Factor Is Required for the Development and Differentiation of Invariant NKT Cells

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Eomes Transcription Factor Is Required for the Development and Differentiation of Invariant NKT Cells ARTICLE https://doi.org/10.1038/s42003-019-0389-3 OPEN Eomes transcription factor is required for the development and differentiation of invariant NKT cells Kanako Shimizu1,3, Yusuke Sato1,3, Masami Kawamura1, Hiroshi Nakazato1, Takashi Watanabe2, 1234567890():,; Osamu Ohara2 & Shin-ichiro Fujii1,2 Eomes regulates the differentiation of CD8+ T cells into effector and memory phases. However, its role in invariant (i)NKT cells remains unknown. Here, we show the impact of Eomes on iNKT cells in the thymus and peripheral tissue using conditional knockout (Eomes- cKO) mice. In the thymus, CD1d-tetramer+CD24+CD44−NK1.1−CD69+stage 0 iNKT cells express higher levels of Eomes than the other iNKT stages. We also found that Eomes regulates NKT1 cell differentiation predominantly. Interestingly, the expression of Eomes in the steady state is low, but can be upregulated after TCR stimulation. We also showed epigenetic changes in the Eomes locus after activation. In addition, vaccination of C57BL/6, but not Eomes-cKO mice with iNKT ligand-loaded dendritic cells generated KLRG1 +iNKT cells in lung, characterized as effector memory phenotype by transcriptome profiling. Thus, Eomes regulates not only the differentiation of NKT1 cells in the thymus, but also their differentiation into memory-like KLRG1+iNKT cells in the periphery. 1 Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan. 2 Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan. 3These authors contributed equally: Kanako Shimizu, Yusuke Sato. Correspondence and requests for materials should be addressed to K.S. (email: [email protected]) or to S.-i.F. (email: [email protected]) COMMUNICATIONS BIOLOGY | (2019) 2:150 | https://doi.org/10.1038/s42003-019-0389-3 | www.nature.com/commsbio 1 ARTICLE COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-019-0389-3 nvariant (i)NKT cells express an invariant T cell antigen we analyzed T cell-specific Eomes-deficient mice, specifically receptor (TCR) α-chain and recognize a complex consisting of CD4-Cre Eomesf/f (Eomes cKO) mice. Conventional CD4+ T cell I + the antigen-presenting MHC-like molecule CD1d and a and CD8 T cell development in the thymus of Eomes cKO mice glycolipid1,2. Recent discoveries of key transcription factors and was unaffected, as assessed by cell numbers and ratios of thy- gene-expression programs have contributed to a deeper under- mocyte subsets, which were similar to those of wild type mice standing of the iNKT cell lineage3. In the commitment to the (Supplementary Fig. 1a). The CD4+ to CD8+ T cell ratio in the NKT cell lineage, iNKT precursors are positively selected by CD4 spleen of Eomes cKO mice was also relatively normal (Supple- +CD8+ thymocytes which express CD1d-glycolipod complexes4. mentary Fig. 1a), consistent with a previous report15. However, After the selection, the TCR signaling initially activates the cal- the frequency of iNKT cells in thymus, spleen, and liver of Eomes cineurin pathway and stimulates the transcription factors, NFAT cKO mice was lower than in WT controls (Fig. 1a). Closer ana- and Egr25. Then, Egr2 activates PLZF as the iNKT cell master lysis of the thymus revealed that the frequency and absolute regulator and also induces the common β subunit of the IL-2/IL- number of CD24−CD44−NK1.1-stage 1 and CD44+NK1.1− 15 receptor (CD122). This leads to the subsequent steps of iNKT stage 2, iNKT cells were increased, but those of CD44+NK1.1+ cell development, composed of cytokine expression and pro- stage 3 iNKT cells were decreased (Fig. 1b, c and Supplementary liferation in response to the IL-15-CD122 axis6. Functional sub- Fig. 2a). Since thymic iNKT cells contain CD4+CD8− single sets of iNKT cells, NKT1, NKT2, and NKT17, have been reported positive and CD4−CD8− double negative subsets, we analyzed to arise during the thymus to peripheral differentiation stages. CD4 and CD8 expression. No change in the ratio of CD4 single The key transcription factors for NKT1, NKT2 and NKT17 positive and CD4−CD8− double negative subsets was observed in development have been identified as T-bet, Gata3 and Rorγt, Eomes cKO mice (Supplementary Fig. 2b). Of note, Eomes cKO respectively3. However, these iNKT cell subsets can also undergo mice expressed higher levels of Vα14TCR than WT controls, further differentiation in the periphery. clearly indicating that the development of iNKT cells in the We previously reported that a population of Klrg1+ iNKT cells thymus was impaired (Fig. 1d and Supplementary Fig. 3). These elicited after administration of α-GalCer-pulsed DCs (DC/Gal) results suggested that the terminal maturation of iNKT cells in are long-lived. These cells predominantly express the NKT1-like the thymus may depend on Eomes expression. Recent studies cytokine IFN-γ, cytotoxic molecules (FasL and granzyme A/B) have suggested that iNKT cell precursors in the thymus receive and in particular express Eomes. Moreover when transferred to the strongest TCR signal during selection rather than mature iNKT cell-deficient mice, they can respond to the same antigen iNKT cells16,17. Therefore, we assessed the level of Eomes in NKT quickly and robustly as a secondary memory type response7. stages 0 to 3 in the thymus by quantitative PCR (qPCR). To However, the molecular mechanism by which the Klrg1+ iNKT isolate stage 0 iNKT cells as iNKT precursor cells, we sorted population is generated after administration of DC/Gal remains CD1d-tetramer+CD24+CD44−NK1.1−CD69+ cells. As shown in unknown. Fig. 1e, stage 0 iNKT cells showed the highest expression of Eomesodermin (Eomes) is a T-box transcription factor with Eomes compared to the other stages. Thus, the expression of high homology to T-bet and is expressed by activated CD8+ Eomes may be related to TCR signaling in the thymus. T cells as well as in resting and activated NK cells8. Eomes is not expressed by naïve T cells, but plays an important role in the formation of conventional memory CD8+ T cells9. In particular, Loss of Eomes decreases NKT1 cells. Recently, iNKT cells have Eomes favours the development of central memory cells, char- been categorized into three lineages based on their master tran- acterized by longer survival and the important potential for scription factors. T-bet is critical for iNKT cell terminal homeostatic proliferation10. In addition, Eomes functions as a maturation and NKT1 generation, whereas Gata3 and Rorγt are master regulator of cell-mediated immunity capable of control- crucial transcription factors for NKT2 and NKT17 differentiation, ling the expression of genes encoding essential effector molecules, respectively3,17–20. We analyzed the expression of several tran- such as IFN-γ, granzyme B, perforin, CXCR3, and CXCR49–13.In scription factors related to iNKT cell differentiation, such as T- addition, Eomes has recently been shown to regulate a specific bet, Gata3, Rorγt as well as the master regulator of all iNKT cells, population of CD8+ T cells in the thymus14. This population, PLZF (Fig. 2a). We also analyzed the expression level of Eomes in which is called IL-4-induced innate memory CD8+ T cells shows iNKT subsets (NKT0, NKT1, NKT2, and NKT17) in the thymus striking upregulation of Eomes but not the related T-box factor, of WT mice. As shown in Fig. 2b, NKT0 express Eomes at higher T-bet14. These findings suggest additional independent roles for levels than other NKT cell subsets. Eomes cKO iNKT cells Eomes in the regulation of particular T cell populations in both expressed higher levels of PLZF and Gata3 protein, but decreased the thymus and peripheral tissues. However the function of levels of T-bet (Fig. 2a–c). Because of the block in the develop- Eomes by itself in iNKT cells remains to be demonstrated. ment of iNKT precursors into NKT1 cells, the frequency of NKT2 To this end, through studies of T cell-specific Eomes condi- and NKT17 subsets tended to increase in the thymus. We then tional knockout (Eomes-cKO) mice, we found that Eomes assessed the phenotypes of iNKT cells in the thymus and spleen, selectively played a role in NKT1 cell development in the thymus. which should be affected by these transcription factors. NK1.1, This impaired development of NKT1 cells in Eomes cKO mice NKG2D, CD69, and CD122, a component of the IL-15 receptor are due to a cell-autonomous effect, as demonstrated by bone that is important for iNKT terminal maturation15, were detected marrow (BM) chimera study. Furthermore, when activated, the in WT mice but their expression was decreased in Eomes cKO remaining iNKT cells in the peripheral tissues in Eomes cKO iNKT cells (Fig. 2d). By contrast, expression of IL-17Rb, which is mice are functionally impaired. The current study reveals the an IL-25 receptor that defines the IL-4 producing capacity of importance of Eomes in the development of NKT1 cells in the iNKT cells21, was substantially increased in Eomes cKO thymus and also in their activation and differentiation in per- iNKT cells (Fig. 2d). ipheral tissues. To better understand Eomes-mediated regulation of the differentiation of iNKT cells, we examined the expression of cytokines, chemokines, and transcription factors in thymic Results iNKT cells by RNA sequencing (RNA-seq). Compared to WT Eomes affects the development of iNKT cells in the thymus.To mice, Eomes cKO mice showed decreased expression of NKT1- investigate the potential role of Eomes in iNKT cell development, related chemokines (Ccl5
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