Mycobacterium bovis and BCG induce different patterns of cytokine and chemokine production in dendritic cells and differentiation patterns in CD4+ T cells

Abstract

Mycobacterium tuberculosis can infect dendritic cells (DCs), but the molecular mechanism by which these cells contribute to tuberculosis pathogenesis is largely unclear. Using Mycobacterium bovis and the attenuated strain M. bovis BCG as model strains, we analysed cytokine and chemokine secretion in murine DCs infected with M. bovis and BCG at 6, 12 and 24 h post-infection. BCG enhanced production of MCP-1, RANTES, IL-12, TNF-a and IL-6 in DCs, while M. bovis promoted secretion of IL-1b, IL-10 and IL-23. Heat-killed BCG and M. bovis both stimulated cytokine production, but at significantly lower concentrations than corresponding live bacteria. Quantitative RT-PCR and Western blotting indicated that NF-kB regulates production of most cytokines and chemokines. After DCs were infected for 24 h, the culture was used to activate naïve CD4 + T cells. A combination of the supernatant and activated DCs infected with M. bovis gave high expression of foxp3 and IL-10, directing differentiation of naïve CD4 + T cells into regulatory T cells (CD4 + CD25 + Foxp3 + ) more effectively than BCG. Furthermore, M. bovis-infected DC cultures induced CD4 + T cells to express significantly higher levels of IL-17, a Th17-type cytokine, while BCG-infected DC cultures stimulated an apparently higher production of IFN-c, a Th1-type cytokine. In addition, the mycobacteria did not exert a direct effect on the differentiation of CD4 + T cells. These differential cytokine profiles in DCs and CD4 + T cells, and the resultant development of CD4 + T subsets, may be related to the pathogenesis of tuberculosis.

Immunomodulatory effects of heat-killed Mycobacterium obuense on human blood dendritic cells

“…Our observation is in accordance with a previous report whereby treating Mo-DCs with HK BCG or HK M. bovis for 24 h stimulated their production of CCL5 and TNF-a. 57 Given our data showing that TLR1 and TLR2 are involved in mediating DC responses to HK M. obuense, a previous study has also demonstrated the ability of the specific TLR1/2 ligand, Pam3CSK4, to enhance the production of CXCL8, IL-6 and TNF-a by purified total blood DCs. 58 IFN-a, a cytokine reported to be mainly released in high amounts by pDCs upon activation of their TLRs, 59 was not detectable in supernatants from both unstimulated and M. obuense-stimulated purified total blood DC cultures.…”

Immune Responses to Bacillus Calmette–Guérin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?

“…Strikingly, IL-4 is secreted at large concentrations indicating that its presence could shift immunity from a T h 1 polarized response toward a T h 2 response, potentially affecting BCG efficacy (62). However, recent studies disproved this hypothesis by showing that BCG-infected DCs cocultured with T cells are capable of inducing T cell proliferation and IFNγ secretion in vitro , the defined T h 1 cytokine critical for the control of M.tb (63). However, IFNγ is shown to correlate poorly with protection against mycobacteria infection and disease (64, 65).…”

Signaling through RIG-I and type I interferon receptor: Immune activation by Newcastle disease virus in man versus immune evasion by Ebola virus (Review)

“…Following the recognition of small viral RNAs, RIG-I elicits signaling cascades, which eventually lead to the activation of the nuclear factor (NF)-κB and IRF-3 TFs. NF-κB regulates the production of most cytokines and chemokines (26), while IRF-3 is central to the development of an antiviral state through the induction of antiviral genes (27). The rapid and robust expression of type I IFN genes is a prerequisite for the induction of numerous antiviral proteins that modulate protein synthesis, growth arrest and apoptosis (28).…”