Les Cellules Folliculaires Dendritiques (FDC) régulent l'homéostasie des lymphocytes B et sont indispensables à la mise en place des réponses immunes humorales. Les FDC s'organisent, au sein des organes lymphoïdes secondaires, en réseaux tridimensionnels denses, nécessaires à leur fonctionnement. Les études s'intéressant aux FDCs, empruntent classiquement des approches in vitro ou ex vivo, peu adaptées à la nature de ce type cellulaire. Au cours de mon travail de thèse, nous avons utilisé plusieurs systèmes de 'multicolor fate mapping' dans le but de déchiffrer in situ les mécanismes à l'origine du développement initial, et du remodelage des réseaux de FDCs en contexte inflammatoire. Nous avons démontré que les FDCs provenaient de la prolifération clonale et de la différentiation des Cellules Marginales Réticulaires (MRC), un autre sous-type cellulaire stromal résidant près des sinus sous-capsulaires ganglionnaires, et dont les fonctions étaient à ce jour, inconnues. Lors des réponses immunes, nous avons prouvé que les FDCs nouvellement formées, ne dérivaient ni du recrutement de progéniteurs circulants ni de la prolifération de FDCs matures, mais plutôt de la prolifération clonale des MRCs, suivie de leur différentiation en FDCs. Au-delà de l'étude de la biologie des FDCs, notre travail a révélé une fonction importante des MRCs dans le soutien de la plasticité des réseaux de FDCs. / Follicular Dendritic Cells (FDCs) regulate B cell function and development of high affinity antibody responses but little is known about their biology. FDCs associate in intricate cellular networks within secondary lymphoid organs. In vitro and ex vivo methods may thus be of little interest to understand the genuine immunobiology of FDCs in their native habitat. Herein, we utilised various multicolor fate mapping systems to investigate the ontogeny and dynamics of lymph node (LN) FDCs in situ. We show that LN FDC networks arise from the clonal expansion and differentiation of Marginal Reticular Cells (MRCs), a population of lymphoid stromal cells lining the LN subcapsular sinus. We further demonstrate that during an immune response, FDCs accumulate in germinal centers and that neither the recruitment of circulating progenitors nor the division of local mature FDCs significantly contributes to this accumulation. In contrast, we provide evidence that newly generated FDCs also arise from the proliferation and differentiation of MRCs, thus unraveling a critical function of this poorly defined stromal cell population.

Follicular dendritic cells (FDCs) reside in primary B-cell follicles and in the light zones of germinal centers (GCs) in secondary follicles, where their dendrites interdigitate forming extensive networks intimately interacting with B-cells. In GCs, FDCs can be found at the edges attached to the supporting reticular fibers. They trap and arrange immune complexes (ICs) in vivo and in vitro in a periodic manner with 200–500Å spacing and provide both antigen-specific and non-specific accessory signals to B-cells. FDCs exist in resting and activated states, with two characteristically different phenotypes. In their activated state, FDCs upregulate the expression of accessory molecules and cytokines important in the FDC-B cell interaction in GCs. We sought to determine the mechanisms influencing the transition of FDCs from a resting to an activated state in GCs and their impact on T-cell dependent (TD) and independent (TI)-GC reactions (GCRs). We found that IC-FDC interactions via FDC-FcgammaRIIB induce the upregulation of FDC-FcgammaRIIB, -ICAM-1, and -VCAM-1, at both the protein and mRNA levels. We also reported for the first time the expression of TLR-4 on FDCs. Moreover, engagement of FDC-TLR4 with LPS activated NF-kappaB, up-regulated expression of important FDC-accessory molecules, including FcgammaRIIB, ICAM-1, and VCAM-1, and enhanced FDC accessory activity in promoting recall IgG responses. Moreover, IC-activated FDCs produced IL-6 and FDC-IL-6 promoted GCRs, somatic hypermutation (SHM) and IgG production. Further, we reported that binding of FDCs to collagen coated surfaces induced restoration of their dendritic processes and networks in vitro. In addition, we designed an FDC-supported in vitro model capable of induction and assessment of primary human antibody responses to protein antigens characterized by class-switching and affinity maturation. Uniquely, we generated TI immune responses to TD protein Ags in the complete absence of T cell help in vivo and in vitro. In the presence of FDC-associated second signals such as BAFF and C4BP, FDC- FcgammaRIIB-periodically trapped-ICs induced the production of Ag-specific IgM, GC-development and plasmablast-differentiation in anti-Thy-1-pretreated nude mice. Purified murine and human B cells cultured in vitro with IC-bearing FDCs also showed the production of antigen–specific IgM within just 48 h.