Sequential Sensing by TLR2 and Mincle Directs Immature Myeloid Cells to Protect against Invasive Group A Streptococcal Infection in Mice

Severe invasive group A Streptococcus (GAS) infection evades anti-bacterial immunity by attenuating the cellular components of innate immune responses. However, this loss of protection is compensated for by interferon (IFN)-γ-producing immature myeloid cells (γIMCs), which are selectively recruited upon severe invasive GAS infection in mice. Here, we demonstrate that γIMCs provide this IFN-γ-mediated protection by sequentially sensing GAS through two distinct pattern recognition receptors. In a mouse model, GAS is initially recognized by Toll-like receptor 2 (TLR2), which promptly induces interleukin (IL)-6 production in γIMCs. γIMC-derived IL-6 promotes the upregulation of a recently identified GAS-sensing receptor, macrophage-inducible C-type lectin (Mincle), in an autocrine or paracrine manner. Notably, blockade of γIMC-derived IL-6 abrogates Mincle expression, downstream IFN-γ production, and γIMC-mediated protection against severe invasive GAS infection. Thus, γIMCs regulate host protective immunity against severe invasive GAS infection via a TLR2–IL-6–Mincle axis. [Display omitted] •γIMCs counteract severe invasive GAS infection by IL-6 and IFN-γ production•γIMCs sequentially sense GAS through two immune receptors, TLR2 and Mincle•TLR2 triggers γIMC-derived IL-6, which mediates Mincle expression and host protection•IFN-γ production is regulated by sequential sensing via the two GAS-sensing receptors Matsumura et al. show that γIMCs sequentially sense group A Streptococcus (GAS) through TLR2 and Mincle. Specifically, TLR2-triggered production of IL-6 functions as an intermediate that amplifies Mincle expression to maximize host protection through IFN-γ production. The sequential sensing is a distinct feature in γIMCs following severe invasive GAS infection.