IL-15 Does Not Affect IEL Development in the Thymus but Regulates Homeostasis of Putative Precursors and Mature CD8αα+ IELs in the Intestine

Lai, Yein Gei; Hou, Mau Sheng; Hsu, Yaw Wen; Chang, Chin Ling; Liou, Yae Huei; Tsai, Ming Han; Lee, Fan; Liao, Nan‐Shih

doi:10.4049/jimmunol.180.6.3757

Cited by 41 publications

(55 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IL-15 is a critical cytokine for the development of IELs 13,18,19 . Previous studies indicated that treatment of CD4 À CD8 À TCRb þ NK1.1 À B220 À CD5 þ cells with IL-15 increased the expression of CD8aa 19,20 . Consistent with these previous reports, IL-15-mediated stimulation of CD4 À CD8 À TCRb þ NK1.1 À B220 À CD5 þ cells from control mice increased the expression of CD8aa (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…IL-15 is critical for the development of TCRab þ CD8aa þ IELs 18,19 . The role of IL-15 in the development of TCRab þ CD8aa þ IELs was suggested by the observation that IL-15 could support the expression of CD8a by the precursors of TCRab þ CD8aa þ IELs in vitro 19,20,23 .…”

Section: Discussionmentioning

confidence: 99%

“…The role of IL-15 in the development of TCRab þ CD8aa þ IELs was suggested by the observation that IL-15 could support the expression of CD8a by the precursors of TCRab þ CD8aa þ IELs in vitro 19,20,23 . Here, we demonstrate that IL-15 failed to cause the expression of CD8a in the precursors of Arnt-deficient TCRab þ CD8aa þ IELs due to low expression of Stat3.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

The ARNT–STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells

et al. 2013

View full text Add to dashboard Cite

Intestinal intraepithelial T cells contribute to the regulation of inflammatory responses in the intestine; however, the molecular basis for their development and maintenance is unknown. The aryl hydrocarbon receptor complexes with the aryl hydrocarbon receptor nuclear translocator (ARNT) and senses environmental factors, including gut microbiota. Here, we identify ARNT as a critical regulator of the differentiation of TCRab þ CD8aa þ intestinal intraepithelial T cells. Mice deficient in either ARNT or aryl hydrocarbon receptor show a greater than-eight-fold reduction in the number of TCRab þ CD8aa þ intestinal intraepithelial T cells. The number of TCRab þ CD8aa þ intestinal intraepithelial T cells is increased by treatment with an aryl hydrocarbon receptor agonist in germ-free mice and is decreased by antibiotic treatment. The Arnt-deficient precursors of TCRab þ CD8aa þ intestinal intraepithelial T cells express low amounts of STAT3 and fail to differentiate towards the TCRab þ CD8aa þ cell fate after IL-15 stimulation, a deficiency that is overcome by overexpression of Stat3. These data demonstrate that the ARNT-STAT3 axis is a critical regulator of TCRab þ CD8aa þ intestinal intraepithelial T-cell development and differentiation.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The ARNT–STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Enhancers neighboring several genes in GO categories involved in leukocyte and lymphocyte activation and cytokine interactions also exhibited significant increases in accessibility with colonization in TCR γδ + IELs (Dataset S10D); these genes include Cd28, Cxcr4, Il15ra, Il2, Il10, Cd40lg, and Ccr7, some of which are associated with the activation of T cells and have been implicated in shaping the IEL compartment. As noted above, IL-15 responsiveness has been shown to be key for the accumulation of CD8αα + TCRβ + cells and also for TCR γδ + cells (25)(26)(27)(28).…”

Section: Significancementioning

confidence: 99%

“…These include ahr, encoding the aryl hydrocarbon receptor (AhR), which controls accumulation of CD8αα + TCRβ + IELs (23); id2, which is required for accumulation of CD8αβ + IELs (24); il15ra (IL15 receptor α), which encodes a component of the IL-15 receptor; and il7r, which specifies a component of the IL-7 receptor. IL-15 and IL-7 are important cytokines controlling the accumulation and function of CD8αα + IELs (25)(26)(27)(28). Additionally, members of two pathways, KEGG "Cell adhesion molecules" (35 genes) and KEGG "ECM-receptor interaction" (25 genes), were also associated with enhancers exhibiting increased accessibility in CONV-R compared to GF TCR αβ + IELs (Dataset S10A); changes in chromatin state affecting enhancers positioned next to genes in these pathways may reflect broad changes in TCR αβ + interactions with the intestinal epithelium upon colonization.…”

Section: Significancementioning

confidence: 99%

Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes

Semenkovich

Planer

Griffin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The gut microbiota impacts many aspects of host biology including immune function. One hypothesis is that microbial communities induce epigenetic changes with accompanying alterations in chromatin accessibility, providing a mechanism that allows a community to have sustained host effects even in the face of its structural or functional variation. We used Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) to define chromatin accessibility in predicted enhancer regions of intestinal αβ + and γδ + intraepithelial lymphocytes purified from germ-free mice, their conventionally raised (CONV-R) counterparts, and mice reared germ free and then colonized with CONV-R gut microbiota at the end of the suckling-weaning transition. Characterizing genes adjacent to traditional enhancers and super-enhancers revealed signaling networks, metabolic pathways, and enhancer-associated transcription factors affected by the microbiota. Our results support the notion that epigenetic modifications help define microbial community-affiliated functional features of host immune cell lineages.gut microbiota-immune cell interactions | ATAC-seq | enhancers of gut intraepithelial lymphocytes | transcription factors | gnotobiotic mice

show abstract

IL‐15 modulates the balance between Bcl‐2 and Bim via a Jak3/1‐PI3K‐Akt‐ERK pathway to promote CD8αα⁺ intestinal intraepithelial lymphocyte survival

Lai

Hou

et al. 2013

Eur J Immunol

Self Cite

View full text Add to dashboard Cite

IL-15 is an essential survival factor for CD8αα+ intestinal intraepithelial lymphocytes + iIEL survival by both increasing Bcl-2 levels and dissociating Bim from Bcl-2 through activation of a Jak3-Jak1-PI3K-Akt-ERK1/2 pathway, which differs from a previously reported IL-15-induced survival signal.Keywords: Bcl-2 r Bim r CD8αα + intestinal intraepithelial lymphocytes (iIELs) r IL-15Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIntestinal intraepithelial lymphocytes (iIELs) are T cells located between the epithelial cells lining the intestinal lumen. In the small intestine of C57BL/6J (B6J) mice, approximately half the iIELs are conventional T cells, while the other half are CD4 − CD8β − CD8α + Correspondence: Dr. Nan-Shih Liao e-mail: mbfelix@imb.sinica.edu.tw (CD8αα + ) cells that consist of 30% TCRαβ + (αβ) cells and 70% TCRγδ + (γδ) cells. CD8αα + iIELs are developmentally and functionally distinct from conventional T cells. Most CD8αα + iIEL precursors go through a thymic stage of development, and complete maturation in the intestine [1][2][3][4]. Functionally, CD8αα + iIELs appear to assume an immune regulatory role in the gut mucosa, as implied by their production of immune suppressive cytokines, such as TGF-β and IL-10, and by their ability to inhibit colitis [5,6]. IL-15 is a pleiotropic cytokine widely expressed with its exclusive high affinity receptor 2306 Yein-Gei Lai et al. Eur. J. Immunol. 2013. 43: 2305-2316 expressed mainly by hematopoietic cells [7][8][9]. IL-15 and IL-15Rα form a complex during synthesis in the ER and exist as transmembrane and soluble forms [10]. The transmembrane IL-15-IL-15Rα complex is "in trans presented" to the IL-15Rβγ on neighboring cells for usage [11]. Fig. 1A and B). Inhibitors of Jak3, PI3K (LY294002), protein kinase B/Akt (Akt) (Akt IV) and MEK (U0126) abolished IL-15's prosurvival, whereas inhibitors of p38 mitogen-activated protein kinase (SB203580) and mammalian target of rapamycin inhibitor (rapamycin) had no effect (Fig. 1B, line graphs). The effective inhibitors diminished IL-15's prosurvival effect in a dose-dependent manner (Supporting Information Fig. 1C). As the αβ and γδ cell composition of CD8αα + iIELs remained the same before and after culturing in medium alone, in IL-15, or in IL-15 plus each inhibitor (Fig. 1B, bar graphs), the IL-15-triggered survival signals are similar in the two subsets at the level of Jak3, PI3K, and ERK1/2 activation. Consistent with the inhibitors' effects on CD8αα + iIEL survival (Fig. 1B), IL-15 induced phosphorylation of Jak1, Akt, and ERK1/2 ( Fig. 1C) with delayed kinetics for ERK1/2 phosphorylation. Moreover, the Jak3 inhibitor abolished Jak1 and Akt phosphorylation, while the PI3K inhibitor did not abolish Jak1 phosphorylation (Fig. 1D). On the other hand, PI3K and Akt inhibitors abolished Akt as well as ERK1/2 phosphorylation, whereas the MEK inhibitor abolished ERK1/2 but not Akt phosphorylation (Fig. 1E). Taken together, IL-15 trigger...

show abstract

IL-15 Does Not Affect IEL Development in the Thymus but Regulates Homeostasis of Putative Precursors and Mature CD8αα+ IELs in the Intestine

Cited by 41 publications

References 36 publications

The ARNT–STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells

The ARNT–STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells

Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes

IL‐15 modulates the balance between Bcl‐2 and Bim via a Jak3/1‐PI3K‐Akt‐ERK pathway to promote CD8αα⁺ intestinal intraepithelial lymphocyte survival

Contact Info

Product

Resources

About

IL-15 Does Not Affect IEL Development in the Thymus but Regulates Homeostasis of Putative Precursors and Mature CD8αα+ IELs in the Intestine

Cited by 41 publications

References 36 publications

The ARNT–STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells

The ARNT–STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells

Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes

IL‐15 modulates the balance between Bcl‐2 and Bim via a Jak3/1‐PI3K‐Akt‐ERK pathway to promote CD8αα+ intestinal intraepithelial lymphocyte survival

Contact Info

Product

Resources

About

IL‐15 modulates the balance between Bcl‐2 and Bim via a Jak3/1‐PI3K‐Akt‐ERK pathway to promote CD8αα⁺ intestinal intraepithelial lymphocyte survival