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    Self-mediated shaping of naïve CD4 T cell effector fate

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    Principal investigator: Cédric Auffray

    Contact :
    Phone : +33 1 40 51 65 89

     

    Objective

     

    T cell precursors originate in the BM and are educated in the thymus through processes called positive and negative selections, which result in MHC-restriction and self-tolerance, respectively. Only those T cells that bear an ab T cell receptor (TCR) recognizing self-MHC with a relatively low affinity will differentiate and exit into the systemic circulation as self-MHC restricted T cells. T cells carrying an ab TCR that reacts with self-MHC with very low affinity die by neglect, whereas those that recognize self-MHC with high affinity are mostly deleted by apoptosis or differentiate into regulatory T cells called "natural" (nTreg) in order to prevent autoimmunity.

    In the periphery, the pre-immune repertoire of T cells is composed of almost 70% of naive T cells. The remaining 30% are divided between recent thymic emigrants with a comparable phenotype, regulatory T cells (Foxp3+) and cells with an activated / memory phenotype. Naive T cells are kept alive through continuous TCR interactions with MHC molecules complexed with various self-peptides. Such TCR/MHC interactions plus contacts with IL-7 cause low-level signaling, which promotes long-term survival of naïve T cells in interphase through synthesis of anti-apoptotic molecules such as Bcl-2.

    In the absence of foreign antigen, peripheral naive T cells continuously recirculate between lymphoid organs, in which they interact frequently and shortly with dendritic cells (DC). The resulting tonic TCR signaling received by CD4 T cells influence their effector fate by increasing quantitatively their responsiveness towards their cognate antigens.

    Following activation by antigen presenting cells (APCs) in the periphery, the bulk of naïve CD4 T cells (CD4 TN cells) can differentiate into a variety of well documented T-helper (TH) cell subsets, such as TH1, TH2, TH17 or induced regulatory T cells (iTreg), characterized by their cytokine production profiles and specific effector functions. The immunological context in which CD4 TN cells are immersed at the time of their activation is known to drive this lineage commitment. Among these effector CD4 T-cell subsets, iTreg cells, whose generation is governed by TGFb, are of particular interest. Indeed, iTreg cells share phenotypic and functional characteristics with nTreg cells that play a crucial role in maintaining peripheral self-tolerance.

    Our recent works reinforce the link between the tonic TCR signaling that the CD4 TN cells receive in the steady state and their fate in the effector phase. We have demonstrated that TCR/self-MHC interactions not only increase quantitatively but also shape qualitatively the response of CD4 TN cells to their cognate antigens in the effector phase. Indeed, we demonstrated that CD4 TN cells with the highest avidity for self-MHC have a biased commitment toward the iTreg cell lineage.

    Altogether, our recent results suggest that continuous / chronic interactions with self-MHC shape both the phenotype of CD4 TN cells and their behavior in the effector phase by favoring their differentiation into iTreg cells. We now plan to extend this study by:

    1. Deciphering the molecular pathways initiated by tonic TCR signaling.
    2. Identifying molecules involved in the higher sensitivity of the most self-reactive CD4 TN cells to iTreg cell polarization signals.
    3. Identifying targets to modulate iTreg cell polarization potential in vivo in different pathological conditions.

     

    The group


    Vincent Guichard, PhD student (University Paris Diderot) is involved in these programs. PhD, Master 1 and Master 2 students and an Engineer (to be recruited) will also be involved in these research projects.

     

    Main publications

     

    Taleb K, Auffray C, Villefroy P, Pereira A, Hosmalin A, Gaudry M, Le Bon A. Chronic Type I IFN Is Sufficient To Promote Immunosuppression through Accumulation of Myeloid-Derived Suppressor Cells. J Immunol. 2017 198(3):1156-1163

    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. Sepsis-induced expansion of granulocytic myeloid-derived suppressor cells promotes tumour growth through Toll-like receptor 4. J Pathol. 2016 239(4):473-83

    Lainé A, Martin B, Luka M, Mir L, Auffray C, Lucas B, Bismuth G, Charvet C. Foxo1 Is a T Cell-Intrinsic Inhibitor of the RORγt-Th17 Program. J Immunol.2015 195(4):1791-803

    Lombes A, Durand A, Charvet C, Rivière M, Bonilla N, Auffray C, Lucas B, Martin B. Adaptive Immune-like γ/δ T Lymphocytes Share Many Common Features with Their α/β T Cell Counterparts. J Immunol.2015 195(4):1449-58

    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

    Carlin LM, Stamatiades EG, Auffray C, Hanna RN, Glover L, Vizcay-Barrena G, Hedrick CC, Cook HT, Diebold S, Geissmann F. Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal. Cell. 2013 153(2):362-75

    Martin B, Auffray C, Delpoux A, Pommier A, Durand A, Charvet C, Yakonowsky P, de Boysson H, Bonilla N, Audemard A, Sparwasser T, Salomon BL, Malissen B, Lucas B. Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells. Nat Commun. 2013 4:2209

    Delpoux A, Poitrasson-Rivière 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

    Auffray C, Fogg DK, Narni-Mancinelli E, Senechal B, Trouillet C, Saederup N, Leemput J, Bigot K, Campisi L, Abitbol M, Molina T, Charo I, Hume DA, Cumano A, Lauvau G, Geissmann F. CX3CR1+ CD115+ CD135+ common macrophage/DC precursors and the role of CX3CR1 in their response to inflammation. J Exp Med. 2009 206:595-606

    Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol. 2009 27:669-92

    Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, Sarnacki S, Cumano A, Lauvau G, Geissmann F. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science. 2007 317(5838):666-70.
     

     

    Financial supports

    These programs are supported by

     

     

     

     

     

     

     

     

     

     

     

     

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