T cells are a key element of the human immune system. Upon binding to antigenic peptides (called T cell epitopes), T cells can induce the death of infected cells or prime and regulate other immune cells. In cancer immunotherapy treatments, T cells are genetically re-engineered to recognize cancer epitopes and destroy malignant cells. Unfortunately, it still remains challenging to determine which T cells can target a specific epitope, both from a computational and experimental point of view. This limits mechanistic understanding of T-cell-mediated immunity and translational applications for disease treatments. Thanks to advances in high-throughput sequencing technologies, sequence data of T cells coupled with their cognate epitopes are accumulating at an unprecedented pace, offering unique opportunities to develop data-driven T cell-epitope interaction predictors. The goal of the MT-PoINT project (Motif in T cells for the Prediction of INTeractions) is to identify patterns in T cells sequences that underlie the binding specificity, interpret them at the structural level, and to develop sequence-based predictors of T cell-epitope interactions (Aim1) with a special focus on T cells targeting cancer epitopes (Aim2). My project will capitalize on a unique dataset of publicly available and in-house generated data that was not available in previous studies, and T cell sequence data from cancer patients of Lausanne University Hospital will allow me to benchmark the in-silico predictors in a clinically relevant setting. Accurate predictions of TCR-epitope interactions can narrow down the list of T cell candidates for personalized cancer immunotherapies, and significantly accelerate cancer immunotherapy clinical developments.

There is increasing awareness that the recently identified cytokine IL-33 is playing a key role in multiple types of infections and pathologies. It has been recently demonstrated that IL-33 is crucial for mounting an efficient immune response against viral infections as it strongly enhances T cell responses with lack of IL-33 leading to failure in virus control. IL-33 production by stromal cells in lymph nodes (LN) and spleen is crucial for efficient viral clearance, however, the precise cellular source and signals involved in secretion of this nuclear alarmin during viral infection are unknown. In addition, it is poorly understood how this cytokine controls antiviral CD8 T cell function. To determine the cellular source of IL-33 during viral infections, we will assess IL-33 production by the different types of stromal cells present in lymph nodes and spleen during acute viral infection. The Luther lab has the expertise and state-of-the-art facilities to perform in situ characterization and in vivo analysis of stromal cell subsets present in these organs, allowing for the identification of the IL-33 producing population. Using IL-33GFP/+ mice will facilitate the identification of the cellular source of IL-33 during viral infections. Moreover, using in vitro cultures we will study the signals regulating IL-33 release as well as its role in T cells function. All together, the work described aims to increase our understanding of the mechanisms underlying stromal IL-33 secretion and its effects on antiviral T cell responses and wishes to broaden our knowledge on the role of stroma cells regulating immune responses. Importantly, this work could have future implications for antiviral treatments, including the development of better strategies for antiviral treatments including vaccines or immunotherapy.

This project aims to study what key institutions and policies are best suited to reduce incentives for engaging in appropriation and armed conflict. For achieving and sustaining peace it is crucial to get the incentives right of all main actors in society. While subproject 1 focuses on short-run policies to stop the fighting by drying out the funding of rebel groups and hence move from war to peace, all the remaining subprojects take a medium- to long-run perspective. Subprojects 2 and 3 focus on the medium-run and assess what mix of policies can help to bridge the short- with the long-run and consolidate peace. In particular, drawing on very fine-grained data from Northern Ireland I will in subproject 2 assess the role and interplay of factors of escalation / containment of violence (“Orange marches”, “peace walls”) and factors driving democratic representation (gerrymandering and power-sharing). In subproject 3 I will perform a network and conflict analysis based on Twitter data for the Arab Spring to assess the role of civil liberties and freedom of speech in consolidating peace. Subprojects 4 to 6 study factors that are crucial for sustaining long-run peace. In subproject 4 I will build a model of how the main political institutions affect the incentives for contesting democracy on the battlefield, focusing on the role of electoral systems, coalition governments, federalism and direct democracy. Subproject 5 studies the role of education for sustaining peace. With the help of a game-theoretic model I will study the various channels through which education affects incentives for conflict, before testing the main predictions empirically. Subproject 6 focuses on another key role of modern states: Health policies. After building a theory of how health affects combat incentives, I will exploit medical innovations to assess the causal impact of health improvement on conflict incentives.

An outstanding challenge at the crossroads of neuro, evolutionary, and developmental biology is explaining how molecular changes give rise to the alternate neural morphologies and physiologies that underlie the behavioral adaptations of animals. I propose to address this by examining the EvoDevo of the olfactory system in insects. The number and physiological properties of olfactory sensory neuron (OSN) populations determine the sensitivity and specificity of olfactory responses. Evolution of new OSN populations requires changes in cell-type diversification, receptor repertoire, receptor regulation, and axonal targeting. However, it is unknown how these factors co-evolve. I will use three complementary methods to investigate the genetic basis of OSN evolution in insects. First, I will utilize the large OSN size in the silk moth to conduct single-cell RNA-seq of OSNs during development, examining transcriptomic differences between related OSN lineages within a species. Second, I will utilize the rapid evolution of the ant olfactory system to investigate comparative gene expression and neurodevelopment in closely related species with divergent olfactory systems. By examining a range of more and less diverged species/OSN populations, I will be able to observe the gene expression changes accompanying OSN evolution. Third, I will test candidate genes by using gene modification in the genetically tractable vinegar fly. This research will show how new OSN circuits evolve, facilitating olfactory system adaptation. More generally, this research will show how genomic changes wrought by evolution can give rise to novel neural circuitries- in essence showing how brains can evolve.