TLR2 Engagement on CD8 T Cells Enables Generation of Functional Memory Cells in Response to a Suboptimal TCR Signal

Staphylococcus aureus infection elicits through its mature lipoproteins an innate immune response by TLR2–MyD88 signaling, which improves bacterial clearing and disease outcome. The role of dendritic cells (DCs) and T cells in this immune activation and the function of T and B cells in defense against S. aureus infection remain unclear. Therefore, we first evaluated DC and T cell activation after infection with S. aureus wild type (WT) and its isogenic mutant, which is deficient in lipoprotein maturation, in vitro. Lipoproteins in viable S. aureus contributed via TLR2–MyD88 to activation of DCs, which promoted the release of IFN-γ and IL-17 in CD4+ T cells. This strong effect was independent of superantigens and MHC class II. We next evaluated the function of T cells and their cytokines IFN-γ and IL-17 in infection in vivo. Six days after systemic murine infection IFN-γ, IL-17, and IL-10 production in total spleen cells were MyD88-dependent and their levels increased until day 21. The comparison of CD3−/−, Rag2−/−, and C57BL/6 mice after infection revealed that IFN-γ and IL-17 originated from T cells and IL-10 originated from innate immune cells. Furthermore, vaccination of mice to activate T and B cells did not improve eradication of S. aureus from organs. In conclusion, S. aureus enhances DC activation via TLR2–MyD88 and thereby promotes TH1 and TH17 cell differentiation. However, neither T cells and their MyD88-regulated products, IFN-γ and IL-17, nor B cells affected bacterial clearing from organs and disease outcome.

Section: Discussionmentioning

confidence: 53%

T and B Cells Are Not Required for ClearingStaphylococcus aureusin Systemic Infection Despite a Strong TLR2–MyD88-Dependent T Cell Activation

Schmaler

Jann

Ferracin

et al. 2011

“…We have demonstrated that TLR2-activated mast cells secrete large amounts of CCL3, which has been demonstrated to be chemotactic for mature NK cells (35) and activated CD8 + T cells (36,37). Our data from in vitro chemotaxis experiments using CCL3 (56). However, the lack of Pam 3 CSK 4 -mediated antitumor effects in Kit W-sh/W-sh mice and their restoration via wild-type, but not TLR2-deficient, mast cells demonstrates a critical role for mast cell TLR2 expression.…”

Section: /2mentioning

confidence: 83%

A Critical Role for Mast Cells and Mast Cell-Derived IL-6 in TLR2-Mediated Inhibition of Tumor Growth

Oldford

Haidl

Howatt

et al. 2010

118

Several TLR agonists are effective in tumor immunotherapy, but their early innate mechanisms of action, particularly those of TLR2 agonists, are unclear. Mast cells are abundant surrounding solid tumors where they are often protumorigenic and enhance tumor angiogenesis. However, antitumor roles for mast cells have also been documented. The impact of mast cells may be dependent on their activation status and mediator release in different tumors. Using an orthotopic melanoma model in wild-type C57BL/6 and mast cell-deficient KitW-sh/W-sh mice and a complementary Matrigel–tumor model in C57BL/6 mice, mast cells were shown to be crucial for TLR2 agonist (Pam3CSK4)-induced tumor inhibition. Activation of TLR2 on mast cells reversed their well-documented protumorigenic role. Tumor growth inhibition after peritumoral administration of Pam3CSK4 was restored in KitW-sh/W-sh mice by local reconstitution with wild-type, but not TLR2-deficient, mast cells. Mast cells secrete multiple mediators after Pam3CSK4 activation, and in vivo mast cell reconstitution studies also revealed that tumor growth inhibition required mast cell-derived IL-6, but not TNF. Mast cell-mediated anticancer properties were multifaceted. Direct antitumor effects in vitro and decreased angiogenesis and recruitment of NK and T cells in vivo were observed. TLR2-activated mast cells also inhibited the growth of lung cancer cells in vivo. Unlike other immune cells, mast cells are relatively radioresistant making them attractive candidates for combined treatment modalities. This study has important implications for the design of immunotherapeutic strategies and reveals, to our knowledge, a novel mechanism of action for TLR2 agonists in vivo.

“…In particular, costimulation through TLR2 triggering lowers the threshold of Ag required for an optimal activation of CD8 + T cells (27). In addition, TLR2-mediated costimulation promotes the development and maintenance of memory T cells (25,28,29). However, whether TLR ligands alone can drive the activation of Ag-experienced T cells is yet to be determined.…”

Section: Tlr-mediated Innate Production Of Ifn-g By Cd8mentioning

confidence: 99%

TLR-Mediated Innate Production of IFN-γ by CD8+ T Cells Is Independent of Glycolysis

Salerno

Guislain

Cansever

et al. 2016

120

CD8+ T cells can respond to unrelated infections in an Ag-independent manner. This rapid innate-like immune response allows Ag-experienced T cells to alert other immune cell types to pathogenic intruders. In this study, we show that murine CD8+ T cells can sense TLR2 and TLR7 ligands, resulting in rapid production of IFN-γ but not of TNF-α and IL-2. Importantly, Ag-experienced T cells activated by TLR ligands produce sufficient IFN-γ to augment the activation of macrophages. In contrast to Ag-specific reactivation, TLR-dependent production of IFN-γ by CD8+ T cells relies exclusively on newly synthesized transcripts without inducing mRNA stability. Furthermore, transcription of IFN-γ upon TLR triggering depends on the activation of PI3K and serine-threonine kinase Akt, and protein synthesis relies on the activation of the mechanistic target of rapamycin. We next investigated which energy source drives the TLR-induced production of IFN-γ. Although Ag-specific cytokine production requires a glycolytic switch for optimal cytokine release, glucose availability does not alter the rate of IFN-γ production upon TLR-mediated activation. Rather, mitochondrial respiration provides sufficient energy for TLR-induced IFN-γ production. To our knowledge, this is the first report describing that TLR-mediated bystander activation elicits a helper phenotype of CD8+ T cells. It induces a short boost of IFN-γ production that leads to a significant but limited activation of Ag-experienced CD8+ T cells. This activation suffices to prime macrophages but keeps T cell responses limited to unrelated infections.