A defect in the synthesis of Interferon-gamma by the T cells of Complement-C5 deficient mice leads to enhanced susceptibility for tuberculosis

作者：Mashruwala Mary Anne; Smith Amanda K; Lindsey Devin R; Moczygemba Margaret; Wetsel Rick A; Klein John R; Actor Jeffrey K; Jagannath Chinnaswamy^*

来源：Tuberculosis, 2011, 91: S82-S89.

DOI：10.1016/j.tube.2011.10.016

• Mycobacterium tuberculosis
• Complement
• Interferon-gamma
• Anaphylatoxin C5a
• Mouse
• IL-12 and IL-18

Interferon-gamma (IFN gamma) plays a major role during host defense against Mycobacterium tuberculosis (Mtb). T cells produce IFN gamma in response to IL-12 and IL-18 secreted from Mtb infected macrophages. IFN gamma in turn, induces nitric oxide secretion in macrophages that kills Mtb. IFN gamma knockout mice are thus hyper-susceptible to tuberculosis. We reported earlier that Complement-C5 deficient (C5(-/-)) congenic mice are more susceptible to tuberculosis and showed reduced IL-12 synthesis in their macrophages. Using C5(-/-) congenic mice that carry a deletion in the C5 gene and the wild type C5(+/+) mice, we demonstrate here that, the C5(-/-) derived CD3(+) T cells, have an additional defect in the synthesis of IFN gamma. C5(-/-) T cells produced lower levels of IFN gamma upon stimulation by antigen presenting cells (APCs) infected with Mtb or when stimulated directly with a combination of IL-12 and IL-18. The latter was in part due to a reduced phosphorylation of STAT4 following IL-12/IL-18 stimulation. Addition of C5a peptide to IL-12/IL-18 partially restored STAT4 phosphorylation and IFN gamma synthesis in C5(-/-) T cells indicating that IL-12/IL-18 mediated signaling within CD3(+) T cells involves C5a peptide. Finally, C5(-/-) T cells derived from M. bovis BCG or Mtb infected mice showed a reduced expression of T-bet (T-box expressed in T cells) transcription factor, which correlated well with a reduced T cell secretion of IFN gamma. Since T-bet mediated IFN gamma synthesis facilitates Th1 expansion, C5(-/-) mouse derived T cells appear to have an intrinsic defect in the production of IFN gamma, which is related to C5 deficiency and this may explain their increased susceptibility to infection with Mtb and BCG.

• 出版日期2011-12