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Molecular Mechanisms for the Regulation of IL-10 Production in T Cells

  • Full or part time
    Dr A O’Garra.
  • Application Deadline
    Tuesday, November 12, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

This 4-year PhD studentship is offered in Dr Anne O’Garra’s Group based at the Francis Crick Institute (the Crick).

Interleukin (IL)-10 is critical for limiting the immune response to pathogens, therefore preventing immunopathology [1]. T cells are an important source of IL-10, with CD4+ T helper (Th)1, Th2, Th17 and T Follicular helper (TFh) cells, producing IL-10 as part of their differentiation pathways [1]. We published that GATA-3 promotes IL-10 expression by remodelling the Il10 gene locus [1]. However, GATA-3 is only expressed in Th2 cells, indicating other mechanisms regulate IL-10 production in other Th cells, but these are not understood. We identified candidate transcription factors by gene expression profiling of IL-10 secreting Th1, Th2 and Th17 cells versus T cells that do not produce IL-10 [3]. We have recently published findings showing that the transcription factor c-Maf is a major regulator of Il10 expression in vivo, in Th1, Th2 and Th17 T cells, which are an important source of IL-10. Our findings also showed that c-Maf is additionally a central disease-specific regulator of gene networks in CD4+ T cells with context specific effects, in part through negative regulation of the cytokine IL-2. Other compelling candidate transcription factors have been defined in the lab, such as Blimp-1 (prdm1), and others, which also appear to contribute to regulation of Il10 gene expression in vitro. This project seeks to determine the relative contribution of Blimp1 and c-Maf on Il10 gene expression both in vitro and in vivo.

The effect of deletion of Blimp-1, c-Maf and double knockouts on IL-10 production in Th1 cells will be studied in vivo, during Toxoplasma gondii infection through intra-peritoneal and oral routes, to determine the regulation of Il10 in lymphoid organs and the gut mucosa respectively (and possibly Helicobacter hepaticus). This will also be compared with Mycobacterium tuberculosis infection where interestingly we saw no effect of deletion of cmaf in CD4+ T cells in vivo on disease phenotype (LMT & AOG unpublished). Effects of transcription factor deletion on IL-10 and Th cell hallmark cytokine expression will be analysed in depth in both lymphoid organs (lymph node/spleen) versus appropriate tissue (gut/lung) respectively similarly to the studies we have recently published with c-Maf [3]. Effects of deletion of each and both transcription factors on Il10 gene expression will be assessed to determine the contribution of both transcription factors on the regulation of Il10 and proinflammatory cytokines in vivo. A systems approach combining gene expression profiling (RNA-Seq, (including single-cell RNA-Seq) of transcription factor mutants versus controls, with ATAC-Seq and possibly genome-wide transcription factor occupancy (ChIP-Seq), and immunological analyses will be used to delineate the role of Blimp-1/c-Maf, and their relative contributions in IL-10 gene regulation against Th hallmark cytokines/effector functions and disease phenotype.

Interleukin-10 expression in Th cells. IL-10 production is associated with the differentiation programmes of each of the CD4+ Th cell subsets and is therefore not a subset specific cytokine. However, the specific signals and transcription factor complexes that determine IL-10 production by the different Th cells and innate cells are poorly understood [2].

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2020 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 13 NOVEMBER 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.

References

1. Saraiva, M. and O'Garra, A. (2010)

The regulation of IL-10 production by immune cells.

Nature Reviews Immunology 10: 170-181. PubMed abstract

2. Gabryšová, L., Howes, A., Saraiva, M. and O'Garra, A. (2014)

The regulation of IL-10 expression.

Current Topics in Microbiology and Immunology 380: 157-190. PubMed abstract

3. Gabryšová, L., Alvarez-Martinez, M., Luisier, R., Cox, L. S., Sodenkamp, J., Hosking, C., . . . O’Garra, A. (2018)

c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells.

Nature Immunology 19: 497-507. PubMed abstract

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