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H2020Individual fellowship2017–2019

CD4CRISPR · A quorum sensing mechanism regulating CD4 T cell proliferation

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2017-04-01 → 2019-03-31
EU contribution
€185,076
Participants
1
Scheme
MSCA-IF

Lines connect the coordinator with its partners.

Results in brief

A quorum sensing mechanism regulating CD4 T cell proliferation

Knowledge about the physiology of the immune response is important for vaccine development. At the core of the adaptive immune response, CD4 T cells are key players of the cellular immunity against pathogens and cancer. The regulation of their proliferation, which is altered during viral infection or in immunosuppressive tumor microenvironments, is a complex and crucial phenomenon underlying the efficiency of the cellular immune response. We have developed an unbiased approach to identify memory CD4 intrinsic inhibitors of proliferation in pathophysiological contexts like chronic infections and cancer. We have restored the mutated CD4 T cells survival and proliferation under an in vivo selective pressure. Identifying mechanisms involved in the inhibition of memory CD4 T cells proliferation is key to the development of long lasting vaccines against pathogens, cancer and also to a better understanding of the mechanisms of autoimmunity.

Data: CORDIS, © European Union

Project objective

The fine and complex regulation of CD4 immune response is important in cancer, autoimmune diseases, inflammatory disorders and viral infection. If signals orchestrating productive CD4 T-cell responses are well documented, the contraction of antigen (Ag)-specific CD4 T-cell populations following the resolution of primary immune response is however not molecularly understood. It has been demonstrated that a negative feedback loop can regulate CD4 T cell proliferation through direct T-T interactions, leading to the preferential exclusion of Ag-experienced T cells. This T cell intrinsic mechanism limits the expansion of effector CD4 T cells and may then interfere with therapeutic vaccine efficacy. Using Cas9-(constitutive/inducible)-expressing Dby-reactive T cells (from a TCR Transgenic RAG-/- mouse strain named Marilyn) coupled to a sgRNA library and an in vivo selection strategy, we will extensively identify the negative regulators of CD4 T cells migration and priming in an ongoing primary immune response. As a proof of concept, we will first inactivate candidate genes (already known to be involved in CD4 T cells negative regulation: TGF-b receptor,IFN-γ receptor, PD-1 and PD-L1) in Ag-experienced memory CD4 T cells, which will be enriched for their proliferative capacity in vivo and used as a second cohort in immunized mice. Then, we will develop a genome-wide screen approach to generate a library of knockout Ag-experienced T cells as a second cohort. We expect that further insight into CD4 suppressive mechanisms, which dampen efficient antitumor immune responses, will allow optimization of cancer immunotherapy.

Original text from CORDIS.

Participants

  • INSTITUT CURIE · ParisCoordinatorFrance

Links

Data: CORDIS, © European Union