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    Physiology of regulatory Foxp3+ CD4 T cells

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    Principal investigator : Bruno Lucas

    Contact : bruno.lucas@inserm.fr – Phone : +33 1 40 51 65 90

     

    Objective

    We have recently demonstrated that Ly-6C expression allows the discrimination of lowly and highly self-reactive regulatory CD4 T cells (Treg cells) in the periphery. Using this new marker, we have obtained data showing that self-recognition events are required to maintain the suppressive capacities and absolute numbers of CD4 Treg cells in the periphery. These unexpected consequences of self-recognition reveal virtuous circles that allow autoreactivity to control its potential harmful consequences such as autoimmunity but that could be detrimental for anti-tumor immunity. Presently, we plan to pursue our work by characterizing the in vivo behavior of highly self-reactive and suppressive CD4 Treg cells in the periphery. Indeed, a greater ability of Ly-6C- CD4 Treg cells to interact with self should have consequences on their behavior in secondary lymphoid organs. Mandl et al. have recently shown that interactions with MHC class II molecules retained CD4 T cells in lymph-nodes (LNs; PNAS 2012. 109: 18036). By using the same protocol [i.e. by blocking T-cell entry into LNs through the i.p. injection of mAbs specific to VLA-4 and LFA-1], we have observed that Treg cells were greatly enriched in the remaining LN CD4 T cells 24 hours after initiating the treatment and that almost all of these Treg cells were Ly-6C-. Thus, 24 hours after entry blockade, very few CD4 TN cells and Ly-6C+ CD4 Treg cells were remaining in LNs whereas a significant proportion of Ly-6C- CD4 Treg cells was still there (20%). More interestingly, we have found that blocking LN entry during 8 days (by repeating the treatment every 2 days) did not result in the exit of these cells from LNs. We thus hypothesize that Treg cells with the highest avidity for self are not continuously recirculating between lymphoid organs but are rather residing permanently in LNs.

    We now plan to extend this experimental observation by:

    1- Characterizing LN-residing Treg cells. Their phenotype, their transcriptional signature, their ability to produce cytokines, their suppressive capacities and their localization and behavior within LNs will be studied.

    2- Defining their specificity. The main question will be: are Treg cells residing in a given LN specific of this LN?

    3- Applying our findings to the case of tumor draining LNs.

    Clarifying these issues will participate in our better understanding of the function of Treg cells.

     

    The group

    Bruno LUCAS, DR1 CNRS, Alexandra Audemard, PhD student (University Paris Descartes), Aurélie Durand, engineer assistant (University Paris Descartes), Nelly Bonilla (TCS, INSERM) and Jean Delmotte (Master 2 Student) are involved in this program.


     

     

    Main publications

    • Llitjos JF, Auffray C, Alby-Laurent F, Rousseau C, Merdji H, Bonilla N, Toubiana J, Belaïdouni N, Mira JP, Lucas B, Chiche JD, Pène F. 2016. Sepsis-induced expansion of granulocytic myeloid-derived suppressor cells promotes tumour growth through Toll-like receptor 4. J Pathol. 239:473-83.
    • Lombes A, Durand A, Charvet C, Rivière M, Bonilla N, Auffray C, Lucas B*, Martin B*. 2015. Adaptive Immune-like γ/δ T Lymphocytes Share Many Common Features with Their α/β T Cell Counterparts. J Immunol. 195:1449-58.
    • Lainé A, Martin B, Luka M, Mir L, Auffray C, Lucas B, Bismuth G, Charvet C. 2015. Foxo1 Is a T Cell-Intrinsic Inhibitor of the RORγt-Th17 Program. J Immunol. 195:1791-803.
    • Delpoux, A., Yakonowsky, P., Durand, A., Charvet, C., Valente, M., Pommier, A., Bonilla, N., Martin, B., Auffray, C.*, Lucas, B.* TCR Signaling Events Are Required for Maintaining CD4 Regulatory T Cell Numbers and Suppressive Capacities in the Periphery J Immunol 2014; 193(12):5914-23
    • Martin, B., Auffray, C., Delpoux, A., Pommier, A., Durand, A., Charvet, C., Yakonowsky, P., de Boysson, H., Bonilla, N., Audemard, A., Sparwasser, T., Salomon, B. L., Malissen, B., Lucas, B. Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells Nat Commun 2013; 4:2209
    • Pommier, A., Audemard, A., Durand, A., Lengagne, R., Delpoux, A., Martin, B., Douguet, L., Le Campion, A., Kato, M., Avril, M. F., Auffray, C., Lucas, B.*, Prevost-Blondel, A.* Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+ T cells Proc Natl Acad Sci U S A 2013; 110(32):13085-90
    • Delpoux, A., Poitrasson-Riviere, M., Le Campion, A., Pommier, A., Yakonowsky, P., Jacques, S., Letourneur, F., Randriamampita, C., Lucas, B.*, Auffray, C.* Foxp3-independent loss of regulatory CD4(+) T-cell suppressive capacities induced by self-deprivation Eur J Immunol 2012; 42(5):1237-49
    • Le Campion, A., Pommier, A., Delpoux, A., Stouvenel, L., Auffray, C., Martin, B.*, Lucas, B.* IL-2 and IL-7 Determine the Homeostatic Balance between the Regulatory and Conventional CD4+ T Cell Compartments during Peripheral T Cell Reconstitution J Immunol 2012; 189(7):3339-46
    • Le Campion, A., Gagnerault, M. C., Auffray, C., Becourt, C., Poitrasson-Riviere, M., Lallemand, E., Bienvenu, B., Martin, B., Lepault, F., Lucas, B. Lymphopenia-induced spontaneous T-cell proliferation as a cofactor for autoimmune disease development Blood 2009; 114(9):1784-93
    • Gagnerault, M. C., Lanvin, O., Pasquier, V., Garcia, C., Damotte, D., Lucas, B., Lepault, F. Autoimmunity during thymectomy-induced lymphopenia: role of thymus ablation and initial effector T cell activation timing in nonobese diabetic mice J Immunol 2009; 183(8):4913-20
    • Wang, Y., Kissenpfennig, A., Mingueneau, M., Richelme, S., Perrin, P., Chevrier, S., Genton, C., Lucas, B., Disanto, J. P., Acha-Orbea, H., Malissen, B., Malissen, M. Th2 Lymphoproliferative Disorder of LatY136F Mutant Mice Unfolds Independently of TCR-MHC Engagement and Is Insensitive to the Action of Foxp3+ Regulatory T Cells J Immunol 2008; 180:1565-1575
    • Poitrasson-Riviere, M., Bienvenu, B., Le Campion, A., Becourt, C., Martin, B., Lucas, B. Regulatory CD4+ T Cells Are Crucial for Preventing CD8+ T Cell-Mediated Autoimmunity J Immunol 2008; 180:7294-304

     

    Financial supports

    This program is supported by the IDEX Sorbonne Paris Cité, the Fondation FRM pour la Recherche Médicale (Equipe Labellisée FRM) and the Fondation ARC pour la Recherche sur le Cancer.


     

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