Toll-like receptor (TLR) 2–9 agonists-induced cytokines and chemokines: I. Comparison with T cell receptor-induced responses

The cells of innate and adaptive immunity, although activated by different ligands, engage in cross talk to ensure a successful immune outcome. To better understand this interaction, we examined the demographic picture of individual TLR (TLRs 2–9) -driven profiles of eleven cytokines (IFN-α/β, IFN-γ, IL-12p40/IL-12p70, IL-4, 1L-13, TNF-α, IL-1β, IL-2, IL-10) and four chemokines (MCP-1, MIP1β, IL-8, and RANTES), and compared them with direct T-cell receptor triggered responses in an assay platform using human PBMCs. We find that T-cell activation by a combination of anti-CD3/anti-CD28/PHA induced a dominant IL-2, IL-13, and Type-II interferon (IFN-γ) response without major IL-12 and little Type-I interferon (IFN-αβ) release. In contrast, TLR7 and TLR9 agonists induced high levels of Type-I interferons. The highest IFN-γ levels were displayed by TLR8 and TLR7/8 agonists, which also induced the highest levels of pro-inflammatory cytokines IL-12, TNF-α, and IL-1β. Amongst endosomal TLRs, TLR7 displayed a unique profile producing weak IL-12, IFN-γ, TNF-α, IL-1β, and IL-8. TLR7 and TLR9 resembled each other in their cytokine profile but differed in MIP-1β and MCP1 chemokine profiles. Gram positive (TLR2, TLR2/6) and gram negative (TLR4) pathogen-derived TLR agonists displayed significant similarities in profile, but not in potency. TLR5 and TLR2/6 agonists paralleled TLR2 and TLR4 in generating pro-inflammatory chemokines MCP-1, MIP-1β, RANTES, and IL-8 but yielded weak TNF-α and IL-1 responses. Taken together, the data show that diverse TLR agonists, despite their operation through common pathways induce distinct cytokine/chemokine profiles that in turn have little or no overlap with TCR-mediated response.