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Re(defining) CD4+ T Cell Identities One Cell at a Time

Re(defining) CD4+ T Cell Identities One Cell at a Time

Objective

The immune system consists of a complex continuum of cell types that communicate with each other and non-immune tissues in homeostasis, and during infections, autoimmunity and cancer. Conventional transcriptional and functional profiling enabled by cell surface marker sorting has revealed a great deal about how specific cell types operate en masse, yet important transcriptional heterogeneity that exists within cell populations remains unexplored. High-throughput single cell RNA-seq can overcome this limitation by profiling entire transcriptomes of thousands of individual cells, revealing cell-to-cell variation by decoding patterns within populations masked in bulk transcriptomes. We will exploit this to dissect the mouse CD4+ T cell compartment, a heterogeneous white blood cell population that initiates adaptive immune responses.
In AIM 1, we will chart the dynamics of in vivo CD4+ cell states in mouse before, during and after immune response challenges. By sequencing thousands of single cell transcriptomes, we will map the landscape of CD4+ T cell states in an unbiased, quantitative and comprehensive way.
In AIM 2, we will predict key transcription factors, cell surface markers, and signalling molecules, including cytokines/chemokines in each cell state through novel computational approaches. Furthermore, our analyses will establish regulatory modules and networks of gene-gene interactions active in immune responses.
In AIM 3, we will (a) confirm the in vivo impact of new cell states by performing adoptive cell transfer assays; and
(b) validate our predictions of regulatory molecules and interactions using a massively parallel CRISPR/Cas knockout screen in vitro.
This powerful integrated approach combines single cell RNA-sequencing, bioinformatics and genetic engineering to dissect CD4+ T cell states, a central compartment of mammalian adaptive immunity, and reveal basic principles of gene regulation.

Host institution

GENOME RESEARCH LIMITED

Address

The Gibbs Building, Euston Road 215
Nw1 2be London

United Kingdom

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 1 778 456,25

Beneficiaries (2)

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GENOME RESEARCH LIMITED

United Kingdom

EU Contribution

€ 1 778 456,25

EUROPEAN MOLECULAR BIOLOGY LABORATORY

Germany

EU Contribution

€ 202 228,75

Project information

Grant agreement ID: 646794

Status

Ongoing project

  • Start date

    1 January 2016

  • End date

    31 December 2020

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 1 980 685

  • EU contribution

    € 1 980 685

Hosted by:

GENOME RESEARCH LIMITED

United Kingdom