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Habilitation À Diriger Des Recherches Year : 2019

From T cell receptor repertoire to systems immunology: an integrative translational approach for biomarkers discovery

CANDIDATURE A L'HABILITATION A DIRIGER DES RECHERCHES Spécialité : IMMUNOLOGIE

Abstract

Since the beginning of my career in academic research, my work has focused on one of the fundamental characteristics of the adaptive immune system, namely the extraordinary diversity of antigen receptors, in particular T-cells, also called TCR (for T-cell Receptor). Indeed, this diversity gives the immune system the potential to recognize the antigenic universe of the "non-self", including pathogens and autologous tumors, even though these antigens are not a priori present in the body. T cells differentiate in the thymus, where they acquire surface expression of the TCR, a heterodimer consisting of two chains, through mechanisms of random somatic rearrangements between several dozen genes present at the genomic level in germline form. Selection steps shape the diversity of differentiated cells, avoiding in particular the export to peripheral sites of cells ineffective in recognizing an antigen, but also and above all eliminating cells, which at random rearrangements could have acquired a TCR capable of recognizing with a very high affinity antigens of the self, and thus contributing to the establishment of a pathological autoimmunity The potential diversity of the repertoire was 10^19 different TCRs (modeled to reach up to 10^61 different TCRs very recently!). Obviously, only a small fraction of the potential repertoire can actually be used, due to the limited number of cells an individual can contain in the body (in humans ~ 10^12 and in mice ~ 10^8 αβ T cells). Once in the periphery, the set of T cells selected in the thymus will constitute the repertoire available for the maintenance of the homeostasis of the organism, involving both cells capable of responding to pathogen infections, allergen intrusion, tumor transformations but also cells capable of avoiding pathological autoimmune manifestations by maintaining tolerance for the self in the periphery. During these immune responses, the available T lymphocyte repertoire will be engaged in the control of the agent to be circumscribed, potentially leading to a modulation, more or less marked, of the diversity of the TCR repertoire. Characterizing these modulations could allow (i) a better understanding of pathological states (e.g. for the development of anti-infective vaccines or tumor cell targeting) and (ii) the identification of biological markers of the pathophysiological state of an individual (e.g. for a better therapeutic management). This diversity of TCRs cannot be dissociated from the diversity of T cell populations now identified on the basis of their respective functions, inflammatory vs. regulatory, intracellular vs. extracellular anti-pathogens, involved in the regulation of antibody production.... Thus, the study of the TCR repertoire only makes sense if we take into account this additional dimension, and consider the immune system as a whole and not simply the sum of its subparts. This approach, now called systems immunology or integrative immunology, has been the foundation of all the research work I have done so far. Thus, my work has focused on (i) the characterization of TCR repertoire modulations under pathological conditions (infection or autoimmune pathology), (ii) the adaptation and improvement of methods for investigating TCR repertoire diversity using molecular biology tools, (iii) the development of statistical modeling strategies of this diversity. This work is based on a systems immunology approach, supported by time and technological developments. My perspectives for the coming years aim at extracting relevant information from the TCR repertoire in the context of autoimmune diseases in particular, by targeting functionally characterized subpopulations, in order to describe their diversity but also to identify TCR signatures associated with pathological situations (in response or not to a treatment). My interest is mainly focused on the balance between regulatory T cells and effector T cells, which is critical for the maintenance of the homeostasis of the organism.
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Dates and versions

tel-03975820 , version 1 (06-02-2023)

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Attribution - NonCommercial - NoDerivatives

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  • HAL Id : tel-03975820 , version 1

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Encarnita Mariotti-Ferrandiz. From T cell receptor repertoire to systems immunology: an integrative translational approach for biomarkers discovery. Adaptive immunology. Sorbonne Université (France), 2019. ⟨tel-03975820⟩
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