IMMUNADAPT · Role of the Nck adaptor proteins in adaptive immune responses

Final Activity Report Summary - IMMUNADAPT (Role of the Nck adaptor proteins in adaptive immune responses)

The overall goal of our work has been to better understand the molecular mechanisms leading to immune tolerance and reactivity. The Nck adaptors have been considered with increasing interest as potential modulators of crucial immunological functions, including signaling of antigen specific immune receptors, cell migration, and inflammation. Their structure, composed of three Src homology (SH)3 domains and a single SH2 domain, enables them to link phosphotyrosine signals to actin cytoskeleton remodelling. Our studies were designed to dissect the role of the Nck proteins in the development and function of dendritic, B and T cells, main cellular players of adaptive immune responses. The EXT funding has enabled to develop the genetic tools necessary to address these questions and carry out the analysis of mice lacking the Nck adaptors in the T cell compartment. T cells defend the organism against microbial infections, while preserving the integrity of healthy tissues, through the development of self-tolerance. These functions are governed by the interaction of the antigen-specific T cell receptor (TCR) with foreign and self-derived peptides presented in the context of major histocompatibility complex (MHC) proteins. In the thymus, "strong" TCR signals result in thymocyte deletion (negative selection), necessary to prevent autoimmune reactions; "moderate" TCR signals lead to T cell survival and differentiation (positive selection); "weak" signals result in death by "neglect". In the peripheral lymphoid organs, mature T cells are maintained through weak interaction with self peptides/MHC complexes, and are activated by strong antigenic stimuli. Our studies provide the first genetic evidence that the Nck adaptors act as amplifiers of TCR signalling, functioning as key regulators of the threshold of T cell responsiveness. By enhancing the sensitivity of T cells to antigenic stimulation, the Nck adaptors enable weak TCR interactions to reach the threshold of positive selection in the thymus and activation in the periphery. At a molecular level, the TCR "desensitisation" of Nck-deficient T cells is associated to CD3e hyper-phosphorylation under resting conditions and reduced ERK phosphorylation and calcium flux upon activation. Taken together, our data demonstrate the novel and crucial role of the Nck adaptors in shaping the T cell repertoire, by ensuring maximal antigenic coverage, peripheral homeostasis and reactivity to foreign antigens. The achievement of these scientific milestones has been possible thanks to the talent and commitment of the young scientists composing the team, the state-of-the-art infrastructure of the Institut Curie, and a number of international collaborations with outstanding scientists. The EXT funding has promoted the scientific development of young scientists, including women of Italo-Argentinian, French and African origin, and the return to Europe of a promising scientist. The acquisition of new technical and scientific skills, through on-site and off-site training as well as the participation to international meetings, has increased the professional know-how of all team members and has provided them with greater international competitiveness. These findings have been successfully presented at several international scientific meetings and have been organised in a manuscript, which is presently being submitted for publication. The interest and novelty of the data should warrant their publication in a high impact journal, ensuring a wide dissemination of the results and increasing the attractiveness and public understanding of science. Furthermore, our data have opened the way to further investigation on the role of the Nck adaptors in T cell tolerance induction, B cell function and on the Nck binding partners, regulating T cell sensitivity to antigenic stimulation. Finally, a long-term medical impact may be foreseen in the screening of patients with immuno-deficiencies of unidentified origin.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз