EpiNKT · Transcriptional and epigenetic control of innate-like T lymphocyte development
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-08-31 → 2017-08-30
- EU contribution
- €164,653
- Participants
- 1
- Scheme
- MSCA-IF-EF-RI
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Results in brief
Transcriptional and epigenetic control of innate-like T lymphocyte development
Natural Killer T (NKT) cells constitute a prototypical population of innate-like T lymphocytes. Their effector programs are acquired during thymic development, prior to microbial exposure, and are polarized into three distinct populations. While the functional heterogeneity of NKT cells is starting to be appreciated, the molecular mechanisms involved in NKT lineage specification and subset polarization are currently not well understood. We recently found that the balance between the E protein family of transcription factors (TF) and their inhibitors, the ID proteins, which is pivotal in the bifurcation of adaptive and innate lymphoid lineages and is associated with human lymphomas, regulates NKT cell development. The overall objective of this grant proposal was to identify genes regulated by the E/ID pathway that determine NKT cell development. NKT cells produce a vast amount of various cytokines rapidly after activation, thereby influencing the functions of innate and adaptive immune cells and orchestrating the early phases of an immune response. Although rare, NKT cells modulate responses to a wide range of diseases, including microbial infection, hematopoietic malignancies, cancer, and inflammation, thus rendering them attractive targets in immune therapies and vaccination strategies. Our studies contribute to the understanding of the developmental and molecular pathways that determine NKT cell effector fate choices and help harness their immunotherapeutic potential. Our studies are therefore relevant to public health because they will provide alternatives for interception of the immune response and thereby alter the course of disease.
Data: CORDIS, © European Union
Project objective
Invariant Natural Killer T (iNKT) cells are a heterogeneous T lymphocyte population that possess innate-like characteristics and contribute to host defense against pathogens. Due to their powerful effector properties, iNKT cells are targeted for immunotherapeutic and vaccination strategies. Their effector programs are acquired during thymic development, prior to microbial exposure, and are polarized into three distinct populations, similar to CD4 Th1, Th2 and Th17 lineages. Specification and subsequent polarization of the NKT lineage is regulated by the balance between the E protein family of transcription factors (TF) and their inhibitors, the ID proteins, which is pivotal in the bifurcation of adaptive and innate lymphoid lineages and is associated with human lymphomas. This application aims at defining the mechanisms by which the E/ID ratio enables the effector properties of innate-like T cells. We hypothesize that the E/ID pathway directly or indirectly regulates critical TFs and chromatin regulators that separately or in combination activate different arms of this effector program. This hypothesis will be tested through the following specific aims: 1) Determine target genes bound by E proteins,2) Determine the epigenetic chromatin states and3) Determine the role of chromatin modifiersin developing iNKT cells. While each aim can be accomplished independently, the data will be integrated to form gene regulatory networks that control the innate-like effector programs. The proposal is innovative because it explores the novel idea that the activity thresholds of a single TF dictate distinct cellular fates, while enhancing our understanding on lymphocyte effector programs and link specific chromatin regulators to these programs. The fellowship is rewarding, because the Applicant will gain knowledge in the implementation of high-throughput technologies to study the interplay between TFs-chromatin regulators-chromatin architecture in lymphocyte differentiation.
Original text from CORDIS.
Participants
- EREVNITIKO KENTRO VIOIATRIKON EPISTIMON ALEXANDROS FLEMINGK · Vari-AthensCoordinatorGreece
Links
Data: CORDIS, © European Union