Responses to mycobacterium tuberculosis infection

Our lab has obtained data on the mechanism of how IL-10 regulates the immune response to MTb infection in mice.

Control and clearance of intracellular pathogens such as MTb is dependent on the production of TNF and the induction of the T-helper 1 (Th1) cytokine IFN-gamma by IL-12. Conversely, IL-10 is a suppressive cytokine essential for dampening the immune response to a number of intracellular pathogens to limit host immune pathology. IL-10 has been shown to exert its suppressive effect by directly acting on the antigen presenting cell (APC), therefore functioning to down-regulate macrophage antimicrobial activity or the induction of Th1 responses by dendritic cells (DC). However, during infection with pathogens such as T. gondii, IL-10 hinders pathogen clearance but is critical for blocking fatal immune pathology. In patients with chronic tuberculosis (TB), T cells are present that produce both IL-10 and IFN-gamma and stimulation of MTb-antigen specific T cells ex-vivo in the presence of anti-IL-10 antibodies results in their increased proliferation and IFN- production. Although this suggests a role for IL-10 in the regulation of the response to MTb, this has not been demonstrated and it is possible that a major role at this stage is to limit immune pathology in chronic disease. To date in murine models of MTb, a role for IL-10 is controversal.

We have identified that IL-10 plays an early and transient role in the control of the immune response to MTb and now show that this involves enhanced migration of IFNgamma producing CD4+ and CD8+ T cells into the lung rather than enhanced mycobacterial killing. The effects are accompanied by enhanced G-CSF, GM-CSF, TNF, IL-6 and IL-17 levels although the enhanced clearance of bacilli in IL-10 deficient mice we now show is independent of IL-17.

The work describing the mechanism of how IL-10 regulates the immune response to MTb infection is now being completed for publication (a manuscript will be submitted for publication in the next few months; Redford, O’Garra et al., 2009). Work on determining the ability of IL-10 depletion to enhance vaccination against MTb infection is being initiated now to continue this programme, but the majority of this work is the scope of the future outside the remits of DC-THERA.

• stimulus type
• mycobacterium tuberculosis,
• toxoplasma gondii

• molecule type
• CD8,
• Interleukin-6,
• Granulocyte macrophage colony-stimulating factor,
• Tumor necrosis factor,
• Interleukin-10,
• Interleukin-12 cytokine,
• Interferon gamma,
• CD4

• organism type
• Mus musculus,
• Homo sapiens

• cell type
• T cell,
• dendritic cell,
• T helper cell 1,
• macrophage

• organ type
• lung

• experimental design type
• ex vivo design experiment

created over 16 years ago (2 March 2009)    last modified over 13 years ago (28 September 2011)   [ RDF ]   [ RelFinder ]