* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Grinberg_abstract_Biosketch-Bordeaux
Survey
Document related concepts
Lymphopoiesis wikipedia , lookup
DNA vaccination wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Immune system wikipedia , lookup
Adaptive immune system wikipedia , lookup
Innate immune system wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Sjögren syndrome wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Autoimmunity wikipedia , lookup
Transcript
Selective contributions of NF-B subunits to regulatory T cell biology Abstract Cancers use a wide variety of mechanisms to dampen tumor immune response. Among them, CD4+Foxp3+ regulatory T cells (Tregs) are largely described to inhibit the function of effector cells. Therefore, precisely understanding the mechanisms governing Treg homeostasis may be a valuable strategy to enhance immune responses against cancer. It is established that transcription factor NF-B plays a major role in Treg development; we are now analyzing the role of canonical p65 and c-Rel NF-B subunits in mature Tregs. We found that specific ablation of one or both NF-B subunits in Tregs drove a gradual autoimmune syndrome. This was associated with profound changes in the molecular signature of NF-B deficient Tregs, which down-regulated Treg-associated genes while acquiring an effectorlike phenotype. Mechanistically, ChIP-Seq analyses showed that Foxp3 and NF-kB cooperated to establish a lineage-specific transcriptome. We next explored the role of NF-B in Treg homeostasis during tumor growth. Strikingly, melanoma growth was drastically reduced in mice lacking c-Rel, but not p65, in Tregs. This was associated with an increased effector T cell activation. Moreover, chemical inhibition of c-Rel delayed melanoma growth and potentiated antiPD-1 checkpoint-blockade therapy by impairing the Treg transcriptional program. Our data demonstrate a specific role for each NF-B subunit in Treg function and homeostasis, and highlights a new therapeutic opportunity for the treatment of cancer. Personal statement My long-term objective in research is to explore the cellular and molecular mechanisms driving immune responses and immunological tolerance and their relevance in animal models and human diseases. My academic training in Paris allowed me to have a general overview of multiple fields of biology and health sciences, in particular immunology. I achieved my PhD thesis, as well as a short postdoc, under the supervision of Benoit Salomon and Eliane Piaggio, in the laboratory of David Klatzmann, at the Pitie-Salpetriere Hospital in Paris. My thesis work was focused on the study of the homeostasis of Foxp3+ regulatory T cells (Treg) during autoimmune diabetes and EAE, a murine model for MS. I sought to further explore the molecular mechanisms driving T-cell functions, and by doing so, to enhance my knowledge in the field of molecular immunology. I joined the laboratory of Sankar Ghosh in New York, Chairman of Department of Microbiology and Immunology at Columbia University, New York. The lab is renowned for its expertise in the NFB family of transcription factors. We have generated mice carrying conditional deletions of NFB subunits either in total T cells or specifically in Treg. These innovative models allowed me to decipher the respective roles of each NF-B subunit in the effector and regulatory mechanisms involved in autoimmunity and cancer. After 5 years in New York, I want to further advance in my academic career and look for a new host laboratory in France. I believe that my background may serve as a base for further studies in a new laboratory. I wish to join a dynamic and renowned institution in order to continue my work on the role of NF-B and other signaling pathways in T-cell biology, in particular Treg, during autoimmune and anti-tumor responses.