When Toll-like receptor and T-cell receptor signals collide: a mechanism for enhanced CD8 T-cell effector function

Abstract

Emerging reports reveal that activating Toll-like receptor-2 (TLR2)-MyD88 signals in CD8 T lymphocytes enhances cytokine production and cytotoxicity; however, the signaling pathway remains undefined. In the present study, we examined the physiologic significance and molecular mechanisms involved in this process. We found that TLR2 engagement on T-cell receptor transgenic CD8 OT-1 T cells increased T-bet transcription factor levels consequently, augmenting effector transcript and protein levels both IntroductionThe molecular and cellular bases for the costimulatory effects of Toll-like receptor (TLR) agonists are being gradually unraveled, adding to our understanding of how TLR signals enhance T cell-mediated immune responses. Expressed primarily on cells of the innate immune system, such as dendritic cells (DCs), TLRs recognize microbial-derived molecules. Certain TLRs, such as TLR1 and TLR2, can form heterodimers to facilitate the detection of a broader array of microbes. 1 TLR engagement on professional antigen-presenting cells (APCs) induces their maturation, resulting in the increased expression of costimulatory molecules and cytokines necessary for optimal T-cell activation. 1 Thus, given their potent effects on APCs, TLR agonists are believed to influence T-cell responses principally by stimulating TLRs on cells of the innate immune system. 1,2 However, recent advances by several groups, including ours, indicate that the adjuvant effects of certain TLR agonists may also be attributed to the activation of TLRs and the TLR adapter molecule myeloid differentiation factor (MyD88) directly in T cells. Both CD4 [3][4][5][6][7][8][9][10][11]12,13 T cells express functional TLRs. In CD8 T cells, concomitant engagement of the T-cell receptor (TCR) and TLR3 enhanced interferon-␥ (IFN-␥) production, 10 whereas TLR2 engagement on CD8 T cells increased the expression levels of granzyme B in vitro. 13 We recently reported that TLR2 engagement on CD8 T cells also increased IFN-␥, granzyme B, and perforin production (referred to as effector molecules), and, consequently, enhanced T-cell cytotoxicity both in vivo and in vitro. 12 However, the molecular pathway by which TLR-MyD88 signals in T cells augment effector function is poorly defined. Only recently have studies implicated the PI3K signaling pathway in TLR2-mediated T-cell activation 14 ; however, the molecular mechanisms through which these signals influence activation and cytotoxicity remain largely undefined.Among the various signals involved in T-cell activation, 2 transcription factors, T-bet and eomesodermin (EOMES), profoundly influence CD8 T-cell differentiation into effector cytotoxic T lymphocytes (CTLs). 15 Both these transcription factors can regulate IFN-␥, perforin, and granzyme B transcription, and in their absence, CD8 T cells fail to effectively transition from a naive T cell into an effector or memory cell. 15-17 T-bet expression is known to be induced by signals mediated via the TCR and IFN-␥R; however, additional signals capable of influencing th...

Affinity Thresholds for Naive CD8+ CTL Activation by Peptides and Engineered Influenza A Viruses

“…An implication is that targeting of TLR2 (44), either on the DC or on the T cell, somehow lowers the affinity threshold enabling activation of OT-I CTL. A recent report has suggested that TLR2 signaling can enhance CTL activation and effector function in response to peptide activation (53). It is tempting to speculate that in our model, TLR2 targeting on OT-I lowers the threshold of activation and promotes activation in response to low-affinity E1 and G1 APLs.…”

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

“…TLR2 agonists, such as Pam3CSK4, stimulate activated T cells, thus promoting their proliferation, differentiation and effector function in vitro and in vivo. [67][68][69] It has been shown that TLR2 engagement on CD8 1 T cells increased T-bet transcription in a MyD88-Akt-mTORand protein kinase C-dependent manner. 68 Consistently, Pam3CSK4 application in vivo with transferred tumor Ag-specific CD8 1 T cells results in enhanced therapeutic efficacy in tumor models.…”

“…[67][68][69] It has been shown that TLR2 engagement on CD8 1 T cells increased T-bet transcription in a MyD88-Akt-mTORand protein kinase C-dependent manner. 68 Consistently, Pam3CSK4 application in vivo with transferred tumor Ag-specific CD8 1 T cells results in enhanced therapeutic efficacy in tumor models. 70,71 The expression of TLR3 and TLR9 on human CD8 1 T cells was also demonstrated by some studies.…”

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

“…On top of that, activation of mTOR signaling is required to drive the costimulatory effect of TLR2 triggering to increase the production of effector molecules (36). To investigate whether these signaling pathways are also engaged during TLR-mediated bystander activation of Agexperienced T cells, we measured the phosphorylation of Akt, mTOR and the ribosomal protein S6K1 (S6), a direct target of mTORC1, by flow cytometry 30 min after stimulation with Pam3 or OVA 257-264 peptide.…”