New perspectives on the regulation of germinal center reaction via αvβ8- mediated activation of TGFβ

International audienceTransforming growth factor-β (TGFβ) is a long-known modulator of immune responses but has seemingly contradictory effects on B cells. Among cytokines, TGFβ has the particularity of being produced and secreted in a latent form and must be activated before it can bind to its receptor and induce signaling. While the concept of controlled delivery of TGFβ signaling via α v β8 integrin-mediated activation has gained some interest in the field of mucosal immunity, the role of this molecular mechanism in regulating T-dependent B cell responses is just emerging. We review here the role of TGFβ and its activation, in particular by α v β8 integrin, in the regulation of mucosal IgA responses and its demonstrated and putative involvement in regulating germinal center (GC) B cell responses. We examine both the direct effect of TGFβ on GC B cells and its ability to modulate the functions of helper cells, namely follicular T cells (Tfh and Tfr) and follicular dendritic cells. Synthetizing recently published works, we reconcile apparently conflicting data and propose an innovative and unified view on the regulation of the GC reaction by TGFβ, highlighting the role of its activation by α v β8 integrin

Contribution to continuum estimation in gamma spectrum by observation of local minima

International audienceThis paper presents a method to estimate the continuum of a gamma rays spectrum through the observation of local minima. The method is simple, automatable and has a large scope of application. Indeed, it is not limited by the peaks width, and consequently it is usable with GeHP as well as with scintillators spectra. In the extent where the method exploits signal properties, its operation is easily explainable. It involves a limited set of meaningful parameters for which an adjustment is proposed. The potential of this method is demonstrated through simulations but also through real gamma spectrometry measurements

Baseline removal in spectrometry gamma by observation of local minima

International audienceThis paper presents a Baseline Removal method in the context of spectrometry gamma. The method implements an estimator for the full continuum based on the observation of local minima. This estimator is constructed from the statistical properties of the signal and is therefore easily explainable. The method involves a limited number of fixed parameters, which allows the automation of the process. Moreover, the method is adaptable to any peaks width, which makes it suitable for both HPGe spectrometers and scintillators. Application to real gamma spectrometry measurements are presented, as well as a discussion about the choice of the parameters, for which an adjustment is proposed

Strength and Numbers: The Role of Affinity and Avidity in the ‘Quality’ of T Cell Tolerance

The ability of T cells to identify foreign antigens and mount an efficient immune response while limiting activation upon recognition of self and self-associated peptides is critical. Multiple tolerance mechanisms work in concert to prevent the generation and activation of self-reactive T cells. T cell tolerance is tightly regulated, as defects in these processes can lead to devastating disease; a wide variety of autoimmune diseases and, more recently, adverse immune-related events associated with checkpoint blockade immunotherapy have been linked to a breakdown in T cell tolerance. The quantity and quality of antigen receptor signaling depend on a variety of parameters that include T cell receptor affinity and avidity for peptide. Autoreactive T cell fate choices (e.g., deletion, anergy, regulatory T cell development) are highly dependent on the strength of T cell receptor interactions with self-peptide. However, less is known about how differences in the strength of T cell receptor signaling during differentiation influences the ‘function’ and persistence of anergic and regulatory T cell populations. Here, we review the literature on this subject and discuss the clinical implications of how T cell receptor signal strength influences the ‘quality’ of anergic and regulatory T cell populations

Regulatory T cells promote cancer immune-escape through integrin αvβ8-mediated TGF-β activation

International audienceAbstract Presence of TGFβ in the tumor microenvironment is one of the most relevant cancer immune-escape mechanisms. TGFβ is secreted in an inactive form, and its activation within the tumor may depend on different cell types and mechanisms than its production. Here we show in mouse melanoma and breast cancer models that regulatory T (Treg) cells expressing the β8 chain of αvβ8 integrin (Itgβ8) are the main cell type in the tumors that activates TGFβ, produced by the cancer cells and stored in the tumor micro-environment. Itgβ8 ablation in Treg cells impairs TGFβ signalling in intra-tumoral T lymphocytes but not in the tumor draining lymph nodes. Successively, the effector function of tumor infiltrating CD8 + T lymphocytes strengthens, leading to efficient control of tumor growth. In cancer patients, anti-Itgβ8 antibody treatment elicits similar improved cytotoxic T cell activation. Thus, this study reveals that Treg cells work in concert with cancer cells to produce bioactive-TGFβ and to create an immunosuppressive micro-environment

Plasmacytoid dendritic cells are dispensable for noninfectious intestinal IgA responses in vivo

International audienceIntestinal DCs orchestrate gut immune homeostasis by dampening proinflammatory T-cell responses and inducing anti-inflammatory IgA responses. Although no specific DC subset has been strictly assigned so far to govern IgA response, some candidate subsets emerge. In particular, plasmacytoid DCs (pDCs), which notoriously promote anti-viral immunity and T-cell tolerance to innocuous antigens (Ags), contribute to IgA induction in response to intestinal viral infection and promote T-cell-independent IgA responses in vitro. Here, using two transgenic mouse models, we show that neither short-term nor long-term pDC depletion alters IgA class switch recombination in Peyer's patches and frequency of IgA plasma cells in intestinal mucosa at steady state, even in the absence of T-cell help. In addition, pDCs are dispensable for induction of intestinal IgA plasma cells in response to oral immunization with T-cell-dependent or T-cell-independent Ags, and are not required for proliferation and IgA switch of Ag-specific B cells in GALT. These results show that pDCs are dispensable for noninfectious IgA responses, and suggest that various DC subsets may play redundant roles in the control of intestinal IgA response