The Emerging Role of CD8+ Tissue Resident Memory T (TRM) Cells in Antitumor Immunity: A Unique Functional Contribution of the CD103 Integrin

Cancer immunotherapy is aimed at stimulating tumor-specific cytotoxic T lymphocytes and their subsequent trafficking so that they may reach, and persist in, the tumor microenvironment, recognizing and eliminating malignant target cells. Thus, characterization of the phenotype and effector functions of CD8+ T lymphocytes infiltrating human solid tumors is essential for better understanding and manipulating the local antitumor immune response, and for defining their contribution to the success of current cancer immunotherapy approaches. Accumulating evidence indicates that a substantial subpopulation of CD3+CD8+ tumor-infiltrating lymphocytes are tissue resident memory T (TRM) cells, and is emerging as an activated tumor-specific T-cell subset. These TRM cells accumulate in various human cancer tissues, including non-small-cell lung carcinoma (NSCLC), ovarian and breast cancers, and are defined by expression of CD103 [αE(CD103)β7] and/or CD49a [α1(CD49a)β1] integrins, along with C-type lectin CD69, which most likely contribute to their residency characteristic. CD103 binds to the epithelial cell marker E-cadherin, thereby promoting retention of TRM cells in epithelial tumor islets and maturation of cytotoxic immune synapse with specific cancer cells, resulting in T-cell receptor (TCR)-dependent target cell killing. Moreover, CD103 integrin triggers bidirectional signaling events that cooperate with TCR signals to enable T-cell migration and optimal cytokine production. Remarkably, TRM cells infiltrating human NSCLC tumors also express inhibitory receptors such as programmed cell death-1, the neutralization of which, with blocking antibodies, enhances CD103-dependent TCR-mediated cytotoxicity toward autologous cancer cells. Thus, accumulation of TRM cells at the tumor site explains the more favorable clinical outcome, and might be associated with the success of immune checkpoint blockade in a fraction of cancer patients

Drug development in oncology assisted by noninvasive optical imaging.

International audienceEarly and accurate detection of tumors, like the development of targeted treatments, is a major field of research in oncology. The generation of specific vectors, capable of transporting a drug or a contrast agent to the primary tumor site as well as to the remote (micro-) metastasis would be an asset for early diagnosis and cancer therapy. Our goal was to develop new treatments based on the use of tumor-targeted delivery of large biomolecules (DNA, siRNA, peptides, or nanoparticles), able to induce apoptosis while dodging the specific mechanisms developed by tumor cells to resist this programmed cell death. Nonetheless, the insufficient effectiveness of the vectorization systems is still a crucial issue. In this context, we generated new targeting vectors for drug and biomolecules delivery and developed several optical imaging systems for the follow-up and evaluation of these vectorization systems in live mice. Based on our recent work, we present a brief overview of how noninvasive optical imaging in small animals can accelerate the development of targeted therapeutics in oncology

Hearing children's use of pointing gestures: from pre-linguistic buds to the blossoming of communication skills

International audienceAmong the conventional gestures which appear early in children's development, pointing is observed between 9 and 12 months, shortly before first words. For Clark (1978), the first vocal demonstratives used by children follow pointing as children shift rather fluidly from pre-linguistic to linguistic communication in a sequence of stages from pointing to deictics and lexical words. According to this perspective, pointing corresponds to a transition in the course of acquisition and facilitates access to combinations and early syntax (Bates et al. 1977). However, gestural communication does not totally disappear with the emergence of vocal productions (Marcos 1998). Furthermore, it is still largely used by adults themselves in combination with vocal productions (Guidetti 1998). This paper explores the evolution and fate of pointing gestures in two longitudinal follow-ups of French speaking children between 11 months and 4 years old and their care-takers. Our analyses of the data show that vocal and gestural modalities are associated and complement each other from the very onset of pointing. We categorized all pointing gestures of the children and the adults in order to analyze their functions from their "pre-linguistic" to their co-verbal uses. The two children use more pointing gestures when their MLU is below 2,5, but they still produce an important number of pointing gestures at four when their MLU is above 5 with particular functions similar to those used by the adults and some creative specific uses. Pointing gestures are therefore still functional and continue to enhance the blossoming of their communication skills

Hearing children's use of pointing gestures: from pre-linguistic buds to the blossoming of communication skills

International audienceAmong the conventional gestures which appear early in children's development, pointing is observed between 9 and 12 months, shortly before first words. For Clark (1978), the first vocal demonstratives used by children follow pointing as children shift rather fluidly from pre-linguistic to linguistic communication in a sequence of stages from pointing to deictics and lexical words. According to this perspective, pointing corresponds to a transition in the course of acquisition and facilitates access to combinations and early syntax (Bates et al. 1977). However, gestural communication does not totally disappear with the emergence of vocal productions (Marcos 1998). Furthermore, it is still largely used by adults themselves in combination with vocal productions (Guidetti 1998). This paper explores the evolution and fate of pointing gestures in two longitudinal follow-ups of French speaking children between 11 months and 4 years old and their care-takers. Our analyses of the data show that vocal and gestural modalities are associated and complement each other from the very onset of pointing. We categorized all pointing gestures of the children and the adults in order to analyze their functions from their "pre-linguistic" to their co-verbal uses. The two children use more pointing gestures when their MLU is below 2,5, but they still produce an important number of pointing gestures at four when their MLU is above 5 with particular functions similar to those used by the adults and some creative specific uses. Pointing gestures are therefore still functional and continue to enhance the blossoming of their communication skills

The bile acid deoxycholate elicits defences in Arabidopsis and reduces bacterial infection

Disease has an effect on crop yields, causing significant losses. As the worldwide demand for agricultural products increases, there is a need to pursue the development of new methods to protect crops from disease. One mechanism of plant protection is through the activation of the plant immune system. By exogenous application, 'plant activator molecules' with elicitor properties can be used to activate the plant immune system. These defence-inducing molecules represent a powerful and often environmentally friendly tool to fight pathogens. We show that the secondary bile acid deoxycholic acid (DCA) induces defence in Arabidopsis and reduces the proliferation of two bacterial phytopathogens: Erwinia amylovora and Pseudomonas syringae pv. tomato. We describe the global defence response triggered by this new plant activator in Arabidopsis at the transcriptional level. Several induced genes were selected for further analysis by quantitative reverse transcription-polymerase chain reaction. We describe the kinetics of their induction and show that abiotic stress, such as moderate drought or nitrogen limitation, does not impede DCA induction of defence. Finally, we investigate the role in the activation of defence by this bile acid of the salicylic acid biosynthesis gene SID2, of the receptor-like kinase family genes WAK1-3 and of the NADPH oxidase-encoding RbohD gene. Altogether, we show that DCA constitutes a promising molecule for plant protection which can induce complementary lines of defence, such as callose deposition, reactive oxygen species accumulation and the jasmonic acid and salicylic acid signalling pathways

Tu pointes ou tu tires ?! Annotation sous ELAN des pointages d'un 'entendant vocalo-gestualisant'

International audienceThe aim of the challenge we are presenting in this study is to show that the canonical shape of pointing gestures (extended index, folded fingers) is representative of a specific type of pointing gesture, but that the formal definition could include all types of alignment of three adjacent segments with no movement in the proximal direction (a movement directed towards the elbow when the hand and fingers are extended).This hypothesis needs to be tested and not only do we use formal elements to describe gestures, but gaze, the direction of the head and verbal productions are here included in our analysis. The visual and vocal modalities are viewed as linked and enable us to underline psychological predicates (Mcneil's growth points). We first present the various elements of our annotation procedure, and our categorization of the various pointing gestures we coded (layout, touch, direction, movement, target) and their inclusion in iconic gestures. We also tackle the anaphoric function of pointing gestures and the formal specialization of the gestures used for that function. This study helps us redefine the reference framework associated with pointing gestures (metrical vs topological, main pointing vs secondary pointing, possible specialization of the degrees of freedom in movements) and shows the importance of using micro-annotations for gestures.Le défi présenté ici vise à montrer que la forme canonique d'un pointage (index tendu, doigts repliés) représente un type particulier de pointage, mais qu'on peut étendre la définition formelle à tout alignement de trois segments adjacents pendant une certaine durée qui ne présente pas de mouvement dans un sens proximal à l'alignement (mouvement dirigé vers le coude alors que la main et les doigts sont tendus). Cette hypothèse est à tester et par delà les éléments formels que nous nous donnons pour décrire le geste, le regard, la direction de la tête et le verbal sont évidemment convoqués. Ces deux modalités verbale/vocale et gestuelle sont vues comme un contexte lié qui devrait permettre de mettre en évidence des prédicats psychologiques (growth point de McNeill). Après avoir donné les éléments du protocole d'annotation, nous exposerons brièvement une catégorisation possible de ces pointages (tracé, toucher, direction, mouvement, mire) mais également leurs inclusions dans des gestes iconiques. Nous aborderons également la fonction anaphorique que peut remplir un pointage gestuel et la spécialisation formelle des gestes utilisés à cet usage. Ce dernier point amène à mieux définir le cadre de référence associé aux pointages (métrique vs topologique, pointage principal vs secondaire, spécialisation éventuelle des degrés de liberté en mouvement) et montre l'importance d'une micro-annotation gestuell