?. Gr1, Ter119 ? ) CD122 + NK1.1 + NKp46 + ILC were analyzed by flow cytometry for their expression of c-FLIP and phosphorylation of STAT5

, Apoptotic cells were visualized by flow cytometry by using the FAM-FLICA Caspase 3/7 assay kit from ImmunoChemistry Technologies according to the manufacturer's protocol. The cell permeable, fluorescent inhibitor probe FAM-DEVD-FMK irreversibly binds to active caspases, vol.3

, BM-derived ILC precursors were enriched by depletion of Ter119 ? , CD19 ? , and LyG/Gr1-positive cells using the respective biotinylated antibodies (Ter119, CD19, and Ly6G/Gr1; clones as indicated above) and anti-biotin Dynabeads (Invitrogen) according to the manufacturer's recommendations. Next, the Ter119/CD19/Gr1-depleted cell suspension was labeled with antibodies against CD3, CD4, CD8, CD122, and NK1.1 and FITC-conjugated streptavidin, p.122

D. Facs-vantage, I. Facs-aria, and B. Dickinson, mM L-glutamine (GIBCO Life technologies), 1 mM Na-pyruvate (GIBCO Life technologies), 100 U/ml penicillin/streptomycin, and 1 x primocin (Amaxa) for 9 days. After 4 days of co-culture, 50% of medium was replaced. Two days later cells were moved to a fresh OP9 feeder cell layer. At day 9 of co-culture cells were analyzed by flow cytometry. To block TNF-, FASL-or TRAIL-mediated signaling, 10 µg/ml of anti-TNF (MP6-XT22), anti-FASL (3C82; Enzo), + NK1.1 ? BM ILC precursors were enriched (on average 42%) by fluorescence-activated cell sorting, vol.2, pp.150-151

, FACS-sorted splenic ILC (CD3 ? NKp46 + NK1.1 + ) were stimulated with IL-15 (50 ng/ml) for 16 h or were left untreated. ILC progenitors were sorted using MoFlo Sorter (Beckman Coulter) from BM extracts. RNA isolation from cell cultures and primary cells was performed using QIAshredder and RNeasy Mini Kit (QIAGEN) according to manufacturer's protocol. cDNA was synthetized using the cDNA Synthesis Kit (Life technologies) according to manufacturer's instructions. The cDNA served as a template for the amplification by realtime PCR, Quantitative real-time PCR (RT-qPCR)

, Ubiquitin-conjugating enzyme E2D 2A (UCE) was used as reference gene. Primers: UCE fwd: 5?-AAGAGAATCCACAAGGAATTGAATG-3?, UCE rev: 5?-CAACA GGACCTGCTGA ACACTG-3?. CD95 (FAS) fwd, pp.5-8

, CD95 (FAS) rev: 5´-UCGGAGAUGCUAUUAGUACCUUGAG-3. DR5 (TRAIL-R2) fwd, pp.5-8

T. Rev, FLIP L fwd: 5?-GCAGAAGCUCUCCCAGCA-3; c-FLIP L rev: 5?-UUUGUCCAUGAG UUCAACGUG-3?. c-FLIP R fwd: 5?-UCCAGAAGUACACCCAGUCCA-3?; c-FLIP R rev, pp.5-8

H. Spits, Innate lymphoid cells-a proposal for uniform nomenclature, Nat. Rev. Immunol, vol.13, pp.145-149, 2013.

C. S. Klose, Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages, Cell, vol.157, pp.340-356, 2014.

E. O. Long, H. S. Kim, D. Liu, M. E. Peterson, and S. Rajagopalan, Controlling natural killer cell responses: integration of signals for activation and inhibition, Annu. Rev. Immunol, vol.31, pp.227-258, 2013.

K. Moro, Innate production of T(H)2 cytokines by adipose tissueassociated c-Kit(+)Sca-1(+) lymphoid cells, Nature, vol.463, pp.540-544, 2010.

N. Satoh-takayama, Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense, Immunity, vol.29, pp.958-970, 2008.
URL : https://hal.archives-ouvertes.fr/pasteur-01402754

G. F. Sonnenberg, L. A. Fouser, and D. Artis, Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22, Nat. Immunol, vol.12, pp.383-390, 2011.

C. A. Lindemans, Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration, Nature, vol.528, pp.560-564, 2015.

S. Sawa, ROR?t+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota, Nat. Immunol, vol.12, pp.320-326, 2011.

L. C. Rankin, Complementarity and redundancy of IL-22-producing innate lymphoid cells, Nat. Immunol, vol.17, pp.179-186, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01440245

C. Song, Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation, J. Exp. Med, vol.212, pp.1869-1882, 2015.

F. Vély, Evidence of innate lymphoid cell redundancy in humans, Nat. Immunol, vol.17, pp.1291-1299, 2016.

C. S. Klose and A. Diefenbach, Transcription factors controlling innate lymphoid cell fate decisions, Curr. Top. Microbiol. Immunol, vol.381, pp.215-255, 2014.

Y. Rochman, R. Spolski, and W. Leonard, New insights into the regulation of T cells by gamma(c) family cytokines, Nat. Rev. Immunol, vol.9, pp.480-490, 2009.

N. Satoh-takayama, IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors, J. Exp. Med, vol.207, pp.273-280, 2010.
URL : https://hal.archives-ouvertes.fr/pasteur-00459092

N. D. Huntington, Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1, Nat. Immunol, vol.8, pp.856-863, 2007.

A. Link, Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells, Nat. Immunol, vol.8, pp.1255-1265, 2007.

C. Gil-cruz, Fibroblastic reticular cells regulate intestinal inflammation via IL-15-mediated control of group 1 ILCs, Nat. Immunol, vol.17, pp.1388-1396, 2016.

S. Shalapour, Interleukin-7 links T lymphocyte and intestinal epithelial cell homeostasis, PLoS One, vol.7, p.31939, 2012.

E. Narni-mancinelli, Fate mapping analysis of lymphoid cells expressing the NKp46 cell surface receptor, Proc. Natl Acad. Sci. USA, vol.108, pp.18324-18329, 2011.
URL : https://hal.archives-ouvertes.fr/hal-00672199

M. Irmler, Inhibition of death receptor signals by cellular FLIP, Nature, vol.388, pp.190-195, 1997.

H. Chau, Cellular FLICE-inhibitory protein is required for T cell survival and cycling, J. Exp. Med, vol.202, pp.405-413, 2005.

D. Panayotova-dimitrova, cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis, Cell Rep, vol.5, pp.397-408, 2013.

N. Zhang and Y. He, An essential role for c-FLIP in the efficient development of mature T lymphocytes, J. Exp. Med, vol.202, pp.395-404, 2005.

N. Ueffing, M. Schuster, E. Keil, K. Schulze-osthoff, and I. Schmitz, Upregulation of c-FLIP short by NFAT contributes to apoptosis resistance of short-term activated T cells, Blood, vol.112, pp.690-698, 2008.

M. K. Kennedy, Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice, J. Exp. Med, vol.191, pp.771-780, 2000.

A. Fuchs, Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12-and IL-15-responsive IFN-?-producing cells, Immunity, vol.38, pp.769-781, 2013.

N. Ueffing, Mutational analyses of c-FLIPR, the only murine short FLIP isoform, reveal requirements for DISC recruitment, Cell Death Differ, vol.15, pp.773-782, 2008.

W. E. Carson, A potential role for interleukin-15 in the regulation of human natural killer cell survival, J. Clin. Invest, vol.99, pp.937-943, 1997.

M. Ebbo, A. Crinier, F. Vély, and E. Vivier, Innate lymphoid cells: major players in inflammatory diseases, Nat. Rev. Immunol, vol.17, pp.665-678, 2017.
URL : https://hal.archives-ouvertes.fr/hal-01764670

P. Mirandola, Activated human NK and CD8+ T cells express both TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors but are resistant to TRAIL-mediated cytotoxicity, Blood, vol.104, pp.2418-2424, 2004.

J. P. Lodolce, IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation, Immunity, vol.9, pp.669-676, 1998.

M. L. Robinette, IL-15 sustains IL-7R-independent ILC2 and ILC3 development, Nat. Commun, vol.8, p.14601, 2017.

S. Wirtz, C. Neufert, B. Weigmann, and M. F. Neurath, Chemically induced mouse models of intestinal inflammation, Nat. Protoc, vol.2, pp.541-546, 2007.

A. Kaser, S. Zeissig, and R. S. Blumberg, Inflammatory bowel disease, Annu. Rev. Immunol, vol.28, pp.573-621, 2010.

C. Eftychi, Temporally distinct functions of the cytokines IL-12 and IL-23 drive chronic colon inflammation in response to intestinal barrier impairment, Immunity, vol.51, pp.367-380, 2019.

L. Egea, GM-CSF produced by nonhematopoietic cells is required for early epithelial cell proliferation and repair of injured colonic mucosa, J. Immunol, vol.190, pp.1702-1713, 2013.

J. M. Blander, R. S. Longman, I. D. Iliev, G. F. Sonnenberg, and D. Artis, Regulation of inflammation by microbiota interactions with the host, Nat. Immunol, vol.18, pp.851-860, 2017.

M. Levy, A. A. Kolodziejczyk, C. A. Thaiss, and E. Elinav, Dysbiosis and the immune system, Nat. Rev. Immunol, vol.17, pp.219-232, 2017.

U. Roy, Distinct microbial communities trigger colitis development upon intestinal barrier damage via innate or adaptive immune cells, Cell Rep, vol.21, pp.994-1008, 2017.

J. G. Caporaso, Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample, Proc. Natl Acad. Sci. USA, vol.108, pp.4516-4522, 2011.

N. Segata, Metagenomic biomarker discovery and explanation, Genome Biol, vol.12, p.60, 2011.

J. P. Zackular, The gut microbiome modulates colon tumorigenesis, MBio, vol.4, pp.692-705, 2013.

G. F. Sonnenberg, Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria, Science, vol.336, pp.1321-1325, 2012.

O. Pikovskaya, Cutting edge: eomesodermin is sufficient to direct Type 1 Innate lymphocyte development into the conventional NK lineage, J. Immunol, vol.196, pp.1449-1454, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01438533

B. Kwong, T-bet-dependent NKp46 + innate lymphoid cells regulate the onset of T H 17-induced neuroinflammation, Nat. Immunol, vol.18, pp.1117-1127, 2017.
URL : https://hal.archives-ouvertes.fr/hal-01764672

O. E. Weizman, ILC1 confer early host protection at initial sites of viral infection, Cell, vol.171, p.12, 2017.

C. Vonarbourg and A. Diefenbach, Multifaceted roles of interleukin-7 signaling for the development and function of innate lymphoid cells, Semin. Immunol, vol.24, pp.165-174, 2012.

A. Marçais, The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells, Nat. Immunol, vol.15, pp.749-757, 2014.

L. J. Hall, Natural killer cells protect mice from DSS-induced colitis by regulating neutrophil function via the NKG2A receptor, Mucosal Immunol, vol.6, pp.1016-1026, 2013.

A. S. Rapaport, The inhibitory receptor NKG2A sustains virus-specific CD8 + T cells in response to a lethal poxvirus infection, Immunity, vol.43, pp.1112-1124, 2015.

L. J. Hall, Induction and activation of adaptive immune populations during acute and chronic phases of a murine model of experimental colitis, Dig. Dis. Sci, vol.56, pp.79-89, 2011.

M. E. Shaul and Z. G. Fridlender, Neutrophils as active regulators of the immune system in the tumor microenvironment, J. Leukoc. Biol, vol.102, pp.343-349, 2017.

V. Bronte, Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards, Nat. Commun, vol.7, p.12150, 2016.

H. Katoh, CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis, Cancer Cell, vol.24, pp.631-644, 2013.

M. F. Neurath, Targeting immune cell circuits and trafficking in inflammatory bowel disease, Nat. Immunol, vol.20, pp.970-979, 2019.

Y. Cui, Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation, Mol. Cell Biol, vol.24, pp.8037-8047, 2004.

R. L. Reinhardt, H. Liang, and R. M. Locksley, Cytokine-secreting follicular T cells shape the antibody repertoire, Nat. Immunol, vol.10, pp.385-393, 2009.

P. Mombaerts, RAG-1-deficient mice have no mature B and T lymphocytes, Cell, vol.68, pp.869-877, 1992.

J. J. Peschon, Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice, J. Exp. Med, vol.180, pp.1955-1960, 1994.

T. M. Mccaughtry, Conditional deletion of cytokine receptor chains reveals that IL-7 and IL-15 specify CD8 cytotoxic lineage fate in the thymus, J. Exp. Med, vol.209, pp.2263-2276, 2012.

Y. Zhu, T-bet and eomesodermin are required for T cell-mediated antitumor immune responses, J. Immunol, vol.185, pp.3174-3183, 2010.

S. L. Sanos and A. Diefenbach, Isolation of NK cells and NK-like cells from the intestinal lamina propria, Methods Mol. Biol, vol.612, pp.505-517, 2010.

U. Bank, Triggering endogenous immunosuppressive mechanisms by combined targeting of Dipeptidyl peptidase IV (DPIV/CD26) and Aminopeptidase N (APN/ CD13)-a novel approach for the treatment of inflammatory bowel disease, Int Immunopharmacol, vol.6, pp.1925-1934, 2006.

U. Erben, A guide to histomorphological evaluation of intestinal inflammation in mouse models, Int J. Clin. Exp. Pathol, vol.7, pp.4557-4576, 2014.

P. J. Turnbaugh, A core gut microbiome in obese and lean twins, Nature, vol.457, pp.480-484, 2009.

R. C. Edgar, UPARSE: highly accurate OTU sequences from microbial amplicon reads, Nat. Methods, vol.10, pp.996-998, 2013.

C. Quast, The SILVA ribosomal RNA gene database project: improved data processing and web-based tools, Nucleic Acids Res, vol.41, pp.590-596, 2013.

Q. Wang, G. M. Garrity, J. M. Tiedje, and J. R. Cole, Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy, Appl Environ. Microbiol, vol.73, pp.5261-5267, 2007.

P. J. Mcmurdie and S. Holmes, phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data, PLoS One, vol.8, p.61217, 2013.

H. Wickham, ggplot2: elegant graphics for data analysis, 2016.