Mod-Gaussian convergence and its applications for models of statistical mechanics

In this paper we complete our understanding of the role played by the limiting (or residue) function in the context of mod-Gaussian convergence. The question about the probabilistic interpretation of such functions was initially raised by Marc Yor. After recalling our recent result which interprets the limiting function as a measure of "breaking of symmetry" in the Gaussian approximation in the framework of general central limit theorems type results, we introduce the framework of $L^1$-mod-Gaussian convergence in which the residue function is obtained as (up to a normalizing factor) the probability density of some sequences of random variables converging in law after a change of probability measure. In particular we recover some celebrated results due to Ellis and Newman on the convergence in law of dependent random variables arising in statistical mechanics. We complete our results by giving an alternative approach to the Stein method to obtain the rate of convergence in the Ellis-Newman convergence theorem and by proving a new local limit theorem. More generally we illustrate our results with simple models from statistical mechanics.Comment: 49 pages, 21 figure

PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.

Expansion of antigen-experienced CD8+ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rβ-IL2Rγc membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential

Infection risk dictates immunological divergence among populations in a Mediterranean lizard

The ability of vertebrates to evolve different defence strategies in response to varying parasitism regimes remains poorly understood. Hosts may adopt two different strategies to defend themselves against parasites: tolerance (hosts alleviate the negative fitness consequences of parasite infection) and resistance (hosts strengthen their immune response as parasite burden increases). Both strategies are effective, but fitness has been reported to decline faster in less-tolerant individuals. Here, we assessed the number of splenocytes and the cell-mediated response (proxies for resistance) and body condition (a proxy for tolerance) in four populations of a Greek endemic lizard (Podarcis gaigeae), each exposed to different infection risks (defined as the cumulative effect of parasite burden and duration of exposure). We anticipated that populations with heavy parasite burden would enhance the efficacy of their immune response (resistance) compared to lizards deriving from parasite-poor habitats. We also predicted that populations with longer exposure to parasites would be adopted and be more tolerant. Each factor (duration of exposure and parasite burden) had a distinct effect on the immune response, and thus, our results were rather complicated. Lizards with heavy parasite burden and aperiodic exposure demonstrated resistance, whereas lizards with heavy parasite burden and chronic exposure were more tolerant. Populations with low parasite burden and minimal exposure were more resistant. Our results suggest that the development of some immunological strategies may be differentiated under different infection risks, even within the same species. © 2016 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2016 European Society For Evolutionary Biology

A new methodology for natech (Natural-technological) risk assessment

Natural-technological accidents, or NATECHs, reveal a particular exposure and vulnerability of industrial facilities to extreme, intense or localised natural hazards. This has been confirmed, in a recent past, by events such as the 1999 Izmit earthquake, the 2002 floods in Southeast France, and the 2004 hurricane Katrina in the U.S. In a way, NATECHs can be considered as an invitation to revisit fields of expertise usually featured in accidental risk analysis. Likewise, efforts devoted to risk reduction and emergency response should also benefit from a NATECH-specific look at industrial facilities. Despite a growing body of regulation for industry operation in hazard-prone areas, mitigation efforts still often address NATECH risks with stand-alone actions and mono-disciplinary approach. This paper advocates for a more integrated approach that features several disciplines. These include: engineering science (for risk analysis; structural resistance etc.); organisation sciences and sociology; geosciences and geography; and risk communication. It will present the progress made in ERRA-NATECH on the development of a new risk Analysis Method. This risk analysis method is supposed to answer the following emerging risk issue: how to cope Industry development in areas exposed to natural hazards or disasters: higher hazard potential, higher frequency of accidents

Orthogonal cytokine engineering enables novel synthetic effector states escaping canonical exhaustion in tumor-rejecting CD8+ T cells.

To date, no immunotherapy approaches have managed to fully overcome T-cell exhaustion, which remains a mandatory fate for chronically activated effector cells and a major therapeutic challenge. Understanding how to reprogram CD8 <sup>+</sup> tumor-infiltrating lymphocytes away from exhausted effector states remains an elusive goal. Our work provides evidence that orthogonal gene engineering of T cells to secrete an interleukin (IL)-2 variant binding the IL-2Rβγ receptor and the alarmin IL-33 reprogrammed adoptively transferred T cells to acquire a novel, synthetic effector state, which deviated from canonical exhaustion and displayed superior effector functions. These cells successfully overcame homeostatic barriers in the host and led-in the absence of lymphodepletion or exogenous cytokine support-to high levels of engraftment and tumor regression. Our work unlocks a new opportunity of rationally engineering synthetic CD8 <sup>+</sup> T-cell states endowed with the ability to avoid exhaustion and control advanced solid tumors