Mycobacterium tuberculosis PE27 activates dendritic cells and contributes to Th1-polarized memory immune responses during in vivo infection

Abstract

A gradual understanding of the proline-glutamate (PE) and proline-proline-glutamate (PPE) families, which compromise 10% of the coding regions in the Mycobacterium tuberculosis (Mtb) genome, has uncovered unique roles in host-pathogen interactions. However, the immunological function of PE27 (Rv2769c), the largest PE member, remains unclear. Here, we explored the functional roles and related signaling mechanisms of PE27 in the interaction with dendritic cells (DCs) to shape the T cell response. PE27 phenotypically and functionally induces DC maturation by up-regulating CD80, CD86, MHC class I and MHC class II expression on the DC surface to promote the production of TNF-α, IL-1β, IL-6, and IL-12p70 but not IL-10. Additionally, we found that PE27-mediated DC activation requires the participation of mitogen-activated protein kinases (MAPKs) and nuclear factor κB (NF-κB) signaling pathways. Interestingly, PE27-treated DCs directed naïve CD4(+) T cells to secrete IFN-γ and activate T-bet but not GATA-3. PE27 also induced IFN-γ-producing memory T cell responses in Mtb-infected mice, indicating that PE27 contributes to Th1-polarization. Taken together, these findings suggest that PE27 possesses Th1-polarizing potential through DC maturation and could be useful in the design of TB vaccines.

Keywords: DCs; Dendritic cell; IFN-γ; IL-10; IL-12p70; IL-1β; IL-2; IL-6; MAPKs; Maturation; Mtb; Mycobacterium tuberculosis; NF-κB; PE; PE27; PPE; TNF-α; Th1 polarization; dendritic cells; interferon-γ; interleukin 10; interleukin 12p70; interleukin 2; interleukin 6; interleukin-1β; mitogen-activated protein kinases; nuclear factor κB; proline-glutamate; proline-proline-glutamate; tumor necrosis factor-α.