M. K. Jenkins, E. Khoruts, D. L. Ingulli, S. J. Mueller, R. L. Mcsorley et al., In vivo activation of antigen-specific CD4 T cells, Annu. Rev. Immunol, vol.19, pp.23-45, 2001.

A. A. Itano and M. K. Jenkins, Antigen presentation to naive CD4 T cells in the lymph node, Nat Immunol, vol.4, pp.733-739, 2003.

J. S. Blum, P. Wearsch, and P. Cresswell, Pathways of antigen processing, Annu. Rev. Immunol, vol.31, pp.443-473, 2013.

T. Yamamoto, M. Hattori, and T. Yoshida, Induction of T-cell activation or anergy determined by the combination of intensity and duration of T-cell receptor stimulation, and sequential induction in an individual cell, Immunology, vol.121, pp.383-391, 2007.

O. Acuto and F. Michel, CD28-mediated co-stimulation: a quantitative support for TCR signalling, Nat. Rev. Immunol, vol.3, pp.939-951, 2003.

P. Riha and C. E. Rudd, CD28 co-signaling in the adaptive immune response, Self. Nonself, vol.1, pp.231-240, 2010.

L. Chen and D. B. Flies, Molecular mechanisms of T cell co-stimulation and coinhibition, Nat. Rev. Immunol, vol.13, pp.227-242, 2013.

Y. Huang and R. L. Wange, T cell receptor signaling: beyond complex complexes, J. Biol. Chem, vol.279, pp.28827-28830, 2004.

R. J. Salmond, A. Filby, I. Qureshi, S. Caserta, and R. Zamoyska, T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance, Immunol. Rev, vol.228, pp.9-22, 2009.

D. Zehn, C. King, M. J. Bevan, and E. Palmer, TCR signaling requirements for activating T cells and for generating memory, Cell. Mol. Life Sci, vol.69, pp.1565-1575, 2012.

M. Poltorak, B. Arndt, B. B. Kowtharapu, A. Reddycherla, V. Witte et al.,

J. A. Simeoni, J. Lindquist, A. Saez-rodriguez, E. Ambach, S. Gilles et al.,

O. Germain, V. D. Acuto, F. Bartolo, S. Micheli, J. Loeser et al.,

J. Tasken, M. Neilson, E. Winslow, G. Hur, K. Crabtree et al., TCR activation kinetics and feedback regulation in primary human T cells, Cell Commun. Signal, vol.11, pp.4-14, 2013.

V. Mayya, D. H. Lundgren, S. Hwang, K. Rezaul, L. Wu et al.,

K. Han, Quantitative Phosphoproteomic Analysis of T Cell Receptor Signaling Reveals System-Wide Modulation of Protein-Protein Interactions, Sci. Signal, vol.2, p.46, 2009.

B. De-wet, T. Zech, M. Salek, O. Acuto, and T. Harder, Proteomic characterization of plasma membrane-proximal T cell activation responses, J. Biol. Chem, vol.286, pp.4072-4080, 2011.

C. Brockmeyer, W. Paster, D. Pepper, C. P. Tan, D. C. Trudgian et al., T cell receptor (TCR)-induced tyrosine phosphorylation dynamics identifies THEMIS as a new TCR signalosome component, J. Biol. Chem, vol.286, pp.7535-7547, 2011.

M. Salek, S. Mcgowan, D. C. Trudgian, O. Dushek, B. Wet et al., Quantitative phosphoproteome analysis unveils LAT as a modulator of CD3? and ZAP-70 tyrosine phosphorylation, PLoS One, vol.8, p.77423, 2013.

R. Roncagalli, S. Hauri, F. Fiore, Y. Liang, Z. Chen et al., Quantitative proteomics analysis of signalosome dynamics in primary T cells identifies the surface receptor CD6 as a Lat adaptor-independent TCR signaling hub, Nat. Immunol, vol.15, pp.384-392, 2014.

L. A. Chylek, V. Akimov, J. Dengjel, K. T. Rigbolt, B. Hu et al.,

. Blagoev, Phosphorylation site dynamics of early T-cell receptor signaling, PLoS One, vol.9, p.104240, 2014.

B. Malissen, C. Grégoire, M. Malissen, and R. Roncagalli, Integrative biology of T cell activation, Nat. Immunol, vol.15, pp.790-797, 2014.

G. P. Morris and P. M. Allen, How the TCR balances sensitivity and specificity for the recognition of self and pathogens, Nat. Immunol, vol.13, pp.121-128, 2012.

R. J. Brownlie and R. Zamoyska, T cell receptor signalling networks: branched, diversified and bounded, Nat. Rev. Immunol, vol.13, pp.257-269, 2013.

S. Paul and B. C. Schaefer, A new look at T cell receptor signaling to nuclear factor-?B, Trends Immunol, vol.34, pp.269-281, 2013.

Y. R. Thaker, H. Schneider, and C. E. Rudd, TCR and CD28 activate the transcription factor NF-?B in T-cells via distinct adaptor signaling complexes, Immunol. Lett, vol.163, pp.113-119, 2014.

N. Coudronniere, M. Villalba, N. Englund, and A. Altman, NF-kappa B activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-theta, Proc. Natl. Acad. Sci. U. S. A, vol.97, pp.3394-3399, 2000.

F. Michel, G. Bonnefoy, G. Mangino, S. Mise-omata, and O. Acuto, CD28 as a molecular amplifier extending TCR ligation and signaling capabilities, Immunity, vol.15, pp.935-945, 2001.

J. Yeh, P. Lecine, J. Nunes, S. Spicuglia, P. Ferrier et al., Novel CD28-Responsive Enhancer Activated by CREB / ATF and AP-1 Families in the Human Interleukin-2 Receptor ?-Chain Locus, Mol. Cell. Biol, vol.21, pp.4515-4527, 2001.
URL : https://hal.archives-ouvertes.fr/hal-01614967

A. C. Liberman, D. Refojo, and E. Arzt, Cytokine signaling/transcription factor crosstalk in T cell activation and Th1-Th2 differentiation, Arch. Immunol. Ther. Exp. (Warsz), vol.51, pp.351-365, 2003.

M. Kaiser, G. R. Wiggin, K. Lightfoot, S. S. Arthur, and A. Macdonald, MSK regulate TCR-induced CREB phosphorylation but not immediate early gene transcription, Eur. J. Immunol, vol.37, pp.2583-2595, 2007.

A. Y. Wen, K. M. Sakamoto, and L. S. Miller, The Role of the Transcription Factor CREB in Immune Function, J. Immunol, vol.185, pp.6413-6419, 2010.

A. Sundstedt, M. Sigvardsson, T. Leanderson, G. Hedlund, T. Kalland et al., In vivo anergized CD4+ T cells express perturbed AP-1 and NF-kappa B transcription factors, Proc. Natl. Acad. Sci. U. S. A, vol.93, pp.979-984, 1996.

P. E. Clavijo, K. A. Frauwirth, P. E. Clavijo, K. A. Frauwirth, K. A. Clavijo et al., Anergic CD8+ T Lymphocytes Have Impaired NF-B Activation with Defects in p65 Phosphorylation and Acetylation, J. Immunol, vol.188, pp.1213-1221, 2012.

M. R. Müller and A. Rao, NFAT, immunity and cancer: a transcription factor comes of age, Nat. Rev. Immunol, vol.10, pp.645-656, 2010.

E. Serfling, F. Berberich-siebelt, A. Avots, S. Chuvpilo, S. Klein-hessling et al., NFAT and NF-?B factorsThe distant relatives, Int. J. Biochem. Cell Biol, vol.36, pp.1166-1170, 2004.

H. Oh and S. Ghosh, NF-?B: roles and regulation in different CD4(+) T-cell subsets, Immunol. Rev, vol.252, pp.41-51, 2013.

N. Hermann-kleiter and G. Baier, NFAT pulls the strings during CD4+ T helper cell effector functions, Blood, vol.115, pp.2989-2997, 2010.

I. Baine, B. T. Abe, and F. Macian, Regulation of T-cell tolerance by calcium/NFAT signaling, Immunol. Rev, vol.231, pp.225-240, 2009.

L. Lin, M. Spoor, A. Gerth, S. Brody, and S. Peng, Modulation of Th1 Activation and Inflammation by the NF-?B Repressor Foxj1, Science, vol.303, pp.1017-1020, 2004.

M. Lovatt and M. J. Bijlmakers, Stabilisation of ?-catenin downstream of T cell receptor signalling, PLoS One, vol.5, pp.1-8, 2010.

G. Driessens, Y. Zheng, F. Locke, J. L. Cannon, F. Gounari et al., Betacatenin inhibits T cell activation by selective interference with linker for activation of T cellsphospholipase C-?1 phosphorylation, J. Immunol, vol.186, pp.784-90, 2011.

C. Charvet, P. Auberger, S. Tartare-deckert, A. Bernard, and M. Deckert, Vav1 couples T cell receptor to serum response factor-dependent transcription via a MEK-dependent pathway, J. Biol. Chem, vol.277, pp.15376-15384, 2002.

N. K. Crellin, R. Garcia, O. Hadisfar, S. E. Allan, T. S. Steiner et al., Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells, J. Immunol, vol.175, pp.8051-8059, 2005.

M. M. Tremblay, M. Y. Bilal, and J. C. Houtman, Prior TLR5 induction in human T cells results in a transient potentiation of subsequent TCR-induced cytokine production, Mol. Immunol, vol.57, pp.161-170, 2014.

T. R. Kollmann, O. Levy, R. R. Montgomery, and S. Goriely, Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly, Immunity, vol.37, pp.771-83, 2012.

R. Medzhitov, Toll-like receptors and innate immunity, Nat. Rev. Immunol, vol.1, pp.135-145, 2001.

K. Takeda and S. Akira, Toll-like receptors in innate immunity, Int. Immunol, vol.17, pp.1-14, 2005.

K. Takeda and S. Akira, TLR signaling pathways. Semin. Immunol, vol.16, pp.3-9, 2004.

S. Akira, Toll-like receptor signaling, J. Biol. Chem, vol.278, pp.38105-38108, 2003.

K. Lim and L. M. Staudt, Toll-like receptor signaling, Cold Spring Harb. Perspect. Biol, vol.5, p.11247, 2013.

T. Kawasaki and T. Kawai, Toll-like receptor signaling pathways, Front. Immunol, vol.5, pp.1-8, 2014.

X. Li, S. Jiang, and R. I. Tapping, Toll-like receptor signaling in cell proliferation and survival, Cytokine, vol.49, pp.1-9, 2010.

J. Brown, H. Wang, G. N. Hajishengallis, and M. Martin, TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk, J. Dent. Res, vol.90, pp.417-427, 2011.

T. D. Troutman, J. F. Bazan, and C. Pasare, Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K, Cell Cycle, vol.11, pp.3559-3567, 2012.

K. H. Taniguchi and T. , IRFs : master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors, Nat. Rev. Immunol, vol.6, pp.644-658, 2006.

K. Honda and T. Taniguchi, Toll-like receptor signaling and IRF transcription factors, IUBMB Life, vol.58, pp.290-295, 2006.

J. Mori, T. Vranac, B. Smrekar, M. Cernilec, V. ?. Serbec et al., Chimeric flagellin as the self-adjuvanting antigen for the activation of immune response against Helicobacter pylori, Vaccine, vol.30, pp.5856-5863, 2012.

J. R. Kim, B. C. Holbrook, S. L. Hayward, L. K. Blevins, M. J. Jorgensen et al., Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates, J. Virol, vol.89, pp.7291-7303, 2015.

H. H. Salman, J. M. Irache, and C. Gamazo, Immunoadjuvant capacity of flagellin and mannosamine-coated poly(anhydride) nanoparticles in oral vaccination, Vaccine, vol.27, pp.4784-4790, 2009.

S. B. Mizel and J. T. Bates, Flagellin as an adjuvant: cellular mechanisms and potential, J. Immunol, vol.185, pp.5677-5682, 2010.

G. Caron, D. Duluc, I. Fremaux, P. Jeannin, C. David et al., Direct Stimulation of Human T Cells via TLR5 and TLR7/8: Flagellin and R-848 Up-Regulate Proliferation and IFN-Production by Memory CD4+ T Cells, J. Immunol, vol.175, pp.1551-1557, 2005.

D. Gibbons, P. Fleming, A. Virasami, M. Michel, N. J. Sebire et al., Interleukin-8 (CXCL8) production is a signatory T cell effector function of human newborn infants, Nat. Med, vol.20, pp.1206-1210, 2014.

M. Mccarron and D. J. Reen, Activated human neonatal CD8+ T cells are subject to immunomodulation by direct TLR2 or TLR5 stimulation, J. Immunol, vol.182, pp.55-62, 2009.

J. Saez-rodriguez, L. Simeoni, J. Lindquist, R. Hemenway, U. Bommhardt et al., A logical model provides insights into T cell receptor signaling, PLoS Comput. Biol, vol.3, p.163, 2007.

D. Bai, L. Ueno, and P. Vogt, Akt-mediated regulation of NFkB and the essentialness of NFkB for the oncogenicity of PI3K and Akt, Int J Cancer, vol.125, pp.2863-2870, 2009.

Y. Chiu, C. Lin, C. Chen, K. Huang, K. Tong et al.,

C. Hsu and . Tang, Peptidoglycan Enhances IL-6 Production in Human Synovial Fibroblasts via TLR2 Receptor, Focal Adhesion Kinase, Akt, and AP-1-Dependent Pathway, J. Immunol, vol.183, pp.2785-2792, 2009.

Z. Sun, C. W. Arendt, W. Ellmeier, E. M. Schaeffer, M. J. Sunshine et al., PKC-theta is required for TCRinduced NF-kappaB activation in mature but not immature T lymphocytes, Nature, vol.404, pp.402-407, 2000.

S. M. Wuerzberger-davis and S. Miyamoto, TAK-ling IKK activation, 2010.

, Sci. Signal, vol.3, p.3

A. Adhikari, M. Xu, and Z. J. Chen, Ubiquitin-mediated activation of TAK1 and IKK, Oncogene, vol.26, pp.3214-3226, 2007.

Y. Fan, Y. Yu, Y. Shi, W. Sun, M. Xie et al., Lysine 63-linked polyubiquitination of TAK1 at lysine 158 is required for tumor necrosis factor alpha-and interleukin-1beta-induced IKK/NF-kappaB and JNK/AP-1 activation, J. Biol. Chem, vol.285, pp.5347-5360, 2010.

M. Mellett, P. Atzei, R. Jackson, L. O'neill, and P. N. Moynagh, Mal mediates TLRinduced activation of CREB and expression of IL-10, J. Immunol, vol.186, pp.4925-4935, 2011.

K. Hazeki, K. Nigorikawa, and O. Hazeki, Role of phosphoinositide 3-kinase in innate immunity, Biol. Pharm. Bull, vol.30, pp.1617-1623, 2007.

M. Martin, K. Rehani, R. S. Jope, and S. M. Michalek, Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3, Nat. Immunol, vol.6, pp.777-784, 2005.

C. Härtel, G. Bein, H. Kirchner, and H. Klüter, A human whole-blood assay for analysis of T-cell function by quantification of cytokine mRNA, Scand. J. Immunol, vol.49, pp.649-654, 1999.

C. Elly, S. Witte, Z. Zhang, O. Rosnet, S. Lipkowitz et al., Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation, Oncogene, vol.18, pp.1147-1156, 1999.

L. J. Appleman, F. L. Van-puijenbroek, K. M. Shu, L. M. Nadler, and V. Boussiotis, CD28 costimulation mediates down-regulation of p27kip1 and cell cycle progression by activation of the PI3K/PKB signaling pathway in primary human T cells, J. Immunol, vol.168, pp.2729-2736, 2002.

U. Holzer, W. W. Kwok, G. T. Nepom, and J. H. Buckner, Differential antigen sensitivity and costimulatory requirements in human Th1 and Th2 antigen-specific CD4+ cells with similar TCR avidity, J. Immunol, vol.170, pp.1218-1223, 2003.

K. Schmiedeberg, H. Krause, F. W. Röhl, R. Hartig, G. Jorch et al.,

, T cells of infants are mature, but hyporeactive due to limited Ca2+influx, PLoS One, vol.11, pp.1-27

Z. Borovsky, G. Mishan-eisenberg, E. Yaniv, and J. Rachmilewitz, Serial Triggering of T Cell Receptors Results in Incremental Accumulation of Signaling Intermediates *, vol.277, pp.21529-21536, 2002.

J. Zhang, T. Bardos, D. Li, I. Gal, C. Vermes et al., Regulation of T Cell Activation Threshold by CD28, 2002.

, Costimulation Through Targeting Cbl-b for Ubiquitination, J. Immunol, vol.169, pp.2236-2240

R. G. Labastida-conde, O. Ramírez-pliego, M. Peleteiro-olmedo, D. V. Lopez-guerrero, O. D. Badillo-godinez et al., Flagellin is a Th1 polarizing factor for human CD4 + T cells and induces protection in a murine neonatal vaccination model of rotavirus infection, Vaccine, vol.36, pp.1-10, 2018.

A. C. Palin, V. Ramachandran, S. Acharya, and D. B. Lewis, Human neonatal naive CD4+ T cells have enhanced activation-dependent signaling regulated by the microRNA miR181a, J. Immunol, vol.190, pp.2682-91, 2013.

R. Thomas and R. D'ari, Biological feedback, 1990.
URL : https://hal.archives-ouvertes.fr/hal-00087681

L. Grieco, L. Calzone, I. Bernard-pierrot, B. Kahn-perle, F. Radvanyi et al., Integrative Modelling of the Influence of MAPK Network on Cancer Cell Fate Decision, PLoS Comput. Biol, vol.9, p.1003286, 2013.
URL : https://hal.archives-ouvertes.fr/inserm-02152259

A. Naldi, C. Hernandez, W. Abou-jaoudé, P. T. Monteiro, C. Chaouiya et al., Logical modelling and analysis of cellular regulatory networks with GINsim 3.0, Front. Physiol, vol.9, pp.289-298, 2018.

S. Collombet, C. Van-oevelen, J. L. Ortega, W. Abou-jaoudé, B. D. Stefano et al., Logical modeling of lymphoid and myeloid cell specification and transdifferentiation, Proc. Natl. Acad. Sci, vol.114, pp.5792-5799, 2017.

D. Bérenguier, C. Chaouiya, P. T. Monteiro, A. Naldi, E. Remy et al., Dynamical modeling and analysis of large cellular regulatory networks, Chaos, vol.23, pp.251141-0251149, 2013.

, Author contributions: O. R-J generated and validated the logical models under the supervision of D. T. and performed the experiments under the supervision of A. S. L. A. K. purified cells and performed experiments. W. A. generated the TLR5 molecular map and contributed to the analyses performed with GINsim. D. Y. G. purified cells. C. H. generated the TCR molecular map. O. R-P. assisted in the technical details of cell purification and culture, This project also received funding from SEP-CONACYT-ANUIES-ECOS NORD (M11S01 and M17S02), 2016.