Mycobacterium tuberculosis PPE60 antigen drives Th1/Th17 responses via Toll-like receptor 2–dependent maturation of dendritic cells

Abstract

Targeting of (MTB) PE/PPE antigens that induce type 1 helper T cell (Th1) and Th17 responses represents a crucial strategy for the development of tuberculosis (TB) vaccines. However, only a few PE/PPE antigens induce these responses. Here, we sought to determine how the cell wall-associated antigen PPE60 (Rv3478) activates dendritic cell (DC) maturation and T-cell differentiation. We observed that PPE60 induces DC maturation by augmenting the protein expression of cluster of differentiation 80 (CD80) and CD86 and major histocompatibility complex (MHC) class I and MHC class II on the cell surface. PPE60 also stimulated the production of tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-6, IL-12p70, and IL-23p19 but not IL-10. This induction was mediated by Toll-like receptor 2 (TLR2) and followed by activation of p38, c-Jun N-terminal kinase (JNK), and NF-κB signaling. PPE60 enhanced MHC-II expression and promoted antigen processing by DCs in a TLR2-dependent manner. Moreover, PPE60-stimulated DCs directed naïve CD4 T cells to produce IFN-γ, IL-2, and IL-17A, expanding the Th1 and Th17 responses, along with activation of T-bet and RAR-related orphan receptor C (RORγt) but not GATA-3. Moreover, PPE60 activated the NLRP3 inflammasome followed by caspase-1-dependent IL-1β and IL-18 synthesis in DCs. Of note, pharmacological inhibition of NLRP3 activation specifically attenuated IFN-γ and IL-17A secretion into the supernatant from CD4 T cells cocultured with PPE60-activated DCs. These findings indicate that PPE60 induces Th1 and Th17 immune responses by activating DCs in a TLR2-dependent manner, suggesting PPE60's potential for use in MTB vaccine development.

Mycobacterium avium subsp. paratuberculosis MAP1889c Protein Induces Maturation of Dendritic Cells and Drives Th2-Biased Immune Responses

“…This mouse model was not available in our laboratory. Instead, we observed that MAP1889c-matured DC could induce T cell proliferation when antigen-activated DCs were co-cultured with splenic T cells from Ag85B-immunized mice followed by the addition of Ag85B to the culture media ( Figure 6) as described previously [42]. We confirmed that MAP1889c-matured DCs could induce Th2 responses in vitro.…”

Expression and regulatory networks of Mycobacterium tuberculosis PE/PPE family antigens

“…Interestingly, NT03MA4150, an ortholog of the Mtb MPTR subfamily gene rv0442c, was the only MPTR ortholog without the characteristic polymorphic MPTR C-terminal region identified in the genome of M. avium subsp. 2.2 | The pe/ppe genes are essential for the in vivo and in vitro survival of Mtb Studies have shown that PE/PPE family proteins were associated with the survival of Mtb in vivo and in vitro through regulation of the host immune response (Grover et al, 2018;Su et al, 2018). PPE60…”

Mycobacterial PPE13 activates inflammasome by interacting with the NATCH and LRR domains of NLRP3

“…However, knock-out of TLR2 did not completely abrogate the expression of NLRP3 protein and the secretion of IL-1β induced by PPE60, indicating that other receptors may contribute to NLRP3 inflammasome activation. 46 Interestingly, we found that PPE13 can directly interact with NLRP3 protein, but not with ASC and caspase-1.…”