Lymphocytes T folliculaires helper et VIH : Unis pour le meilleur et pour le pire

International audienceFollicular helper T cells (Tfh) have been discovered in lymph nodes and, since then, are the focus of very intensive research to understand their origin, differentiation and functions. Tfh interact with B cells in the secondary lymphoid organs leading to B cell differentiation and maturation. Tfh are particularly studied in pathological contexts such as autoimmune diseases and infection by the human immunodeficiency virus (HIV). In the context of HIV infection, broadly neutralizing antibodies have been identified in a few patients. The generation of these broadly neutralizing antibodies requires a long and complex maturation of B cells in the secondary lymphoid organs. Characterizing Tfh functions and the relation with the quality of antibodies in HIV infection might help in designing novel immunotherapies and vaccination strategies to induce broadly neutralizing antibodies.Les lymphocytes T folliculaires helper (Tfh) ont été découverts dans les années 2000 et sont, depuis, le sujet d’intenses recherches visant à comprendre leur(s) origine(s), leur(s) différenciation(s) et leurs fonctions. Les Tfh interagissent avec les lymphocytes B (LB) dans les organes lymphoïdes secondaires. Ces interactions permettent la différenciation des LB en cellules produisant des anticorps de haute affinité. Les Tfh sont particulièrement étudiés dans des contextes pathologiques, comme les maladies auto-immunes et l’infection par le virus de l’immunodéficience humaine (VIH). Dans le cas de l’infection par le VIH, des anticorps hautement neutralisants ont été identifiés chez quelques patients. La production de ces anticorps nécessite une maturation longue et complexe des LB. L’étude de la fonction des Tfh, en lien avec la qualité de ces anticorps, pourrait aider à développer de nouvelles immunothérapies et stratégies vaccinales visant à induire des anticorps neutralisants

The NF-κB RelA Transcription Factor Is Critical for Regulatory T Cell Activation and Stability

International audienceRegulatory T cells (Tregs) play a major role in immune homeostasis and in the prevention of autoimmune diseases. It has been shown that c-Rel is critical in Treg thymic differentiation, but little is known on the role of NF-κB on mature Treg biology. We thus generated mice with a specific knockout of RelA, a key member of NF-κB, in Tregs. These mice developed a severe autoimmune syndrome with multi-organ immune infiltration and high activation of lymphoid and myeloid cells. Phenotypic and transcriptomic analyses showed that RelA is critical in the acquisition of the effector Treg state independently of surrounding inflammatory environment. Unexpectedly, RelA-deficient Tregs also displayed reduced stability and cells that had lost Foxp3 produced inflammatory cytokines. Overall, we show that RelA is critical for Treg biology as it promotes both the generation of their effector phenotype and the maintenance of their identity

HIV-Infected Dendritic Cells Present Endogenous MHC Class II–Restricted Antigens to HIV-Specific CD4 + T Cells

International audienceIt is widely assumed that CD4(+) T cells recognize antigenic peptides (epitopes) derived solely from incoming, exogenous, viral particles or proteins. However, alternative sources of MHC class II (MHC-II)-restricted Ags have been described, in particular epitopes derived from newly synthesized proteins (so-called endogenous). In this study, we show that HIV-infected dendritic cells (DC) present MHC-II-restricted endogenous viral Ags to HIV-specific (HS) CD4(+) T cells. This endogenous pathway functions independently of the exogenous route for HIV Ag presentation and offers a distinct possibility for the immune system to activate HS CD4(+) T cells. We examined the implication of autophagy, which plays a crucial role in endogenous viral Ag presentation and thymic selection of CD4(+) T cells, in HIV endogenous presentation. We show that infected DC do not use autophagy to process MHC-II-restricted HIV Ags. This is unlikely to correspond to a viral escape from autophagic degradation, as infecting DC with Nef- or Env-deficient HIV strains did not impact HS T cell activation. However, we demonstrate that, in DC, specific targeting of HIV Ags to autophagosomes using a microtubule-associated protein L chain 3 (LC3) fusion protein effectively enhances and broadens HS CD4(+) T cell responses, thus favoring an endogenous MHC-II-restricted presentation. In summary, in DC, multiple endogenous presentation pathways lead to the activation of HS CD4(+) T cell responses. These findings will help in designing novel strategies to activate HS CD4(+) T cells that are required for CTL activation/maintenance and B cell maturation

B Cells Loaded with Synthetic Particulate Antigens: A Versatile Platform To Generate Antigen-Specific Helper T Cells for Cell Therapy

International audienceAdoptive cell therapy represents a promising approach for several chronic diseases. This study describes an innovative strategy for biofunctionalization of nanoparticles, allowing the generation of synthetic particulate antigens (SPAg). SPAg activate polyclonal B cells and vectorize noncognate proteins into their endosomes, generating highly efficient stimulators for ex vivo expansion of antigen-specific CD4+ T cells. This method also allows harnessing the ability of B cells to polarize CD4+ T cells into effectors or regulators