Abstract
Gram+ infections are worldwide life-threatening diseases in which the pathological role of type I interferon (IFN) has been highlighted. Plasmacytoid predendritic cells (pDCs) produce high amounts of type I IFN following viral sensing. Despite studies suggesting that pDCs respond to bacteria, the mechanisms underlying bacterial sensing in pDCs are unknown. We show here that human primary pDCs express toll-like receptor 1 (TLR1) and 2 (TLR2) and respond to bacterial lipoproteins. We demonstrated that pDCs differentially respond to gram+ bacteria through the TLR1/2 pathway. Notably, up-regulation of costimulatory molecules and pro-inflammatory cytokines was TLR1 dependent, whereas type I IFN secretion was TLR2 dependent. Mechanistically, we demonstrated that these differences relied on diverse signaling pathways activated by TLR1/2. MAPK and NF-κB pathways were engaged by TLR1, whereas the Phosphoinositide 3-kinase (PI3K) pathway was activated by TLR2. This dichotomy was reflected in a different role of TLR2 and TLR1 in pDC priming of naïve cluster of differentiation 4+ (CD4+) T cells, and T helper (Th) cell differentiation. This work provides the rationale to explore and target pDCs in bacterial infection.
Highlights
Tuberculosis (TB) and multidrug-resistant bacteria are a major concern for worldwide health [1]
Among the toll-like receptor (TLR) expressed by plasmacytoid predendritric cell (pDC), toll-like receptor 1 (TLR1) and TLR2 mediate bacterial sensing by binding lipoproteins [8]
We found that pDCs express TLR1 at steady state and TLR2 in a stimulationdependent manner, and that those 2 TLRs are functional for PAM3 sensing
Summary
Tuberculosis (TB) and multidrug-resistant bacteria are a major concern for worldwide health [1]. In TB and gram+ infection, type I interferon (IFN) has been shown to play a pathological role [2,3]. Plasmacytoid pre-dendritic cells (pDCs) are known to produce high amounts of type I IFN in response to viral sensing [4]. It is reported that pDCs are able to respond to gram+ bacteria [5], can be recruited at the site of the infection, and are enriched in TB lymph nodes [6]. Gram+ bacteria express lipoproteins on their surface membrane, which play an important role in their survival and pathogenicity [7]. TLR2 knockout mice are more susceptible to mycobacterial infection, but Mycobacterium tuberculosis is able to hijack TLR2 signaling to enhance its survival in the host [9].
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