Anne O’Garra group
Regulation of the immune response in infectious disease
The immune system is effective in eradicating pathogens via many mechanisms, including soluble mediators called cytokines. Immune cells can produce different cytokines to control infection, but can cause host damage if uncontrolled. We are researching the molecular mechanisms underlying the development and function of discrete subsets of immune cells that produce different cytokines protective against pathogens, and the induction and function of a regulatory cytokine, IL-10. (Figure 1) We use diverse tools to study the mechanisms of IL-10 gene regulation in macrophages, dendritic cells and T cells, and the consequences of IL-10 action in mouse models of infectious diseases, with strong emphasis on tuberculosis (TB) caused by Mycobacterium tuberculosis.
TB is a major cause global cause of morbidity and mortality. Using a systems biology approach we identified a robust blood transcriptional interferon-inducible neutrophil-driven signature in human TB, and longitudinal analysis revealed that this signature disappears during successful treatment (Figure 2). Based on these findings and continued studies in human disease and in cellular and in vivo experimental models (Figure 2), we are continuing to identify immune mechanisms of protection or pathogenesis important for disease control in tuberculosis and other bacterial infections.
Figure 1: Regulation of IL-10 production in immune cells
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Figure 2: Experimental models
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- Saraiva, M and O'Garra, A (2010)
The regulation of IL-10 production by immune cells.
Nature Reviews Immunology 10, 170-181 PubMed abstract
- Berry, MPR; Graham, CM; McNab, FW; Xu, Z; Bloch, SAA; Oni, T; Wilkinson, KA; Banchereau, R; Skinner, J; Wilkinson, RJ; Quinn, C; Blankenship, D; Dhawan, R; Cush, JJ; Mejias, A; Ramilo, O; Kon, OM; Pascual, V; Banchereau, J; Chaussabel, D and O'Garra, A (2010)
An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis.
Nature 466, 973-977 PubMed abstract
- Redford, PS; Boonstra, A; Read, S; Pitt, J; Graham, C; Stavropoulos, E; Bancroft, GJ and O'Garra, A (2010)
Enhanced protection to Mycobacterium tuberculosis infection in IL-10-deficient mice is accompanied by early and enhanced Th1 responses in the lung.
European Journal of Immunology 40, 2200-2210 PubMed abstract
- Kaiser, F; Cook, D; Papoutsopoulou, S; Rajsbaum, R; Wu, X; Yang, HT; Grant, S; Ricciardi-Castagnoli, P; Tsichlis, PN; Ley, SC and O'Garra, A (2009)
TPL-2 negatively regulates interferon-β production in macrophages and myeloid dendritic cells.
Journal of Experimental Medicine 206, 1863-1871 PubMed abstract
- O'Garra, A and Murphy, KM (2009)
From IL-10 to IL-12: how pathogens and their products stimulate APCs to induce TH1 development.
Nature Immunology 10, 929-932 PubMed abstract
- Saraiva, M; Christensen, JR; Veldhoen, M; Murphy, TL; Murphy, KM and O'Garra, A (2009)
Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose.
Immunity 31, 209-219 PubMed abstract
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