Direct Toll‐Like Receptor 8 signaling increases the functional avidity of human CD8+ T lymphocytes generated for adoptive T cell therapy strategies

Chatillon, Jean-François; Hamieh, Mohamad; Bayeux, Florence; Abasq, C.; Fauquembergue, Emilie; Drouet, Aurélie; Guisier, Florian; Latouche, Jean-Baptiste; Musette, Philippe

doi:10.1002/iid3.43

Cited by 5 publications

(4 citation statements)

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“…The functional avidity is one of the crucial determinants of T cell functionality. Although the process of primary T cells regulates their sensitivity to peptide antigen in vitro is disclosed 19 20 21 22 , how VACV tunes the low avidity CD8 + T cells induced by DNA vaccination into high avidity ones in vivo is still not defined. Previously, we had proved that the improved functional avidity of T cells induced by VACV is mediated by intrinsic MyD88 mediated signaling pathways in CD8 + T cells, instead of antigen presentation efficacy, TCR affinity, or the VACV infection induced MyD88-mediated inflammatory milieu 27 .…”

Section: Discussionmentioning

confidence: 99%

“…It’s well shown that an individual T cell clone can be generated into both high- and low-avidity effectors by in vitro stimulation with a high or low concentration of peptide, respectively, which is determined by the initiation of T cell receptor (TCR) signaling 19 20 21 . Moreover, the Toll-like receptor 8 engagement increased anti-tumor cytotoxic T lymphocyte (CTL) functional avidity in vitro 22 . Currently, it’s well demonstrated that T cells could undergo a process called functional avidity maturation when encountered with the antigen, leading to the increased avidity in antigen experienced cells compared to naïve ones 23 .…”

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confidence: 99%

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Immune Signature of Enhanced Functional Avidity CD8+ T Cells in vivo Induced by Vaccinia Vectored Vaccine

Zhu

Wang

et al. 2017

Sci Rep

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Functional avidity of T cells is a critical determinant for clearing viral infection and eliminating tumor. Understanding how functional avidity is maintained in T cells is imperative for immunotherapy. However, studies systematically characterize T cell with high functional avidity induced in vivo are still lacking. Previously, we and others found vaccinia vectored vaccine (VACV) induced antigen-specific CD8+ T cells with relatively high functional avidity to those from DNA vaccine. Herein, we used functional, immune phenotyping and transcriptomic studies to define the immune signature of these CD8+ T cells with high functional avidity. Antigen-specific CD8+ T cells induced by VACV executed superior in vivo killing activity and displayed a distinct transcriptional profile, whereas no significantly differences were found in composition of memory sub-populations and cytokine poly-functionality. Transcriptional analyses revealed unique features of VACV induced CD8+ T cells in several biological processes, including transport, cell cycle, cell communication and metabolic processes. In summary, we characterize CD8+ T cells of high functional avidity induced in vivo by VACV, which not only improves our understanding of adaptive T cell immunity in VACV vaccination, but also provides clues to modulate functional avidity of CD8+ T cells for T cell based immunotherapy.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Immune Signature of Enhanced Functional Avidity CD8+ T Cells in vivo Induced by Vaccinia Vectored Vaccine

Zhu

Wang

et al. 2017

Sci Rep

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“…SelgantolimodNucleotide analogue[44,45] TLR7/TLR8Resiquimod Imidazoquinoline compound derivative[24,38,40] CL075Thiazoloquinolone derivative[29,[46][47][48] …”

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confidence: 99%

The Relevance of TLR8 in Viral Infections

Martínez-Espinoza

Guerrero-Plata

2022

Pathogens

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Toll-like receptors (TLRs) are the largest pattern recognition receptors responsible for activating the innate and adaptive immune response against viruses through the release of inflammatory cytokines and antiviral mediators. Viruses are recognized by several TLRs, including TLR8, which is known to bind ssRNA structures. However, the similarities between TLR8 and TLR7 have obscured the distinctive characteristics of TLR8 activation and its importance in the immune system. Here we discuss the activation and regulation of TLR8 by viruses and its importance in therapeutical options such as vaccine adjuvants and antiviral stimulators.

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“…Acting on different transcriptional repression mechanisms is most likely key factor for efficient reversion of HIV latency (75,76). We tested the hypothesis that prostratin (acting directly on latently infected T cells), in concert with TLR8ag (acting via DCs), disrupts HIV latency (67) and might trigger the priming and restoration of antigen-specific immunity, through costimulatory molecules and IL-12p70 expression (71,77,78). Adding TLR8ag might lead to a Th1 supportive milieu crucial to clear the persistent quiescent reservoir in vivo.…”

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confidence: 99%

Promising Role of Toll-Like Receptor 8 Agonist in Concert with Prostratin for Activation of Silent HIV

Rochat

Schlaepfer

Speck

2017

J Virol

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The persistence of latently HIV-infected cells in patients under combined antiretroviral treatment (cART) remains the major hurdle for HIV eradication. Thus far, individual compounds have not been sufficiently potent to reactivate latent virus and guarantee its elimination in vivo. Thus, we hypothesized that transcriptional enhancers, in concert with compounds triggering the innate immune system, are more efficient in reversing latency by creating a Th1 supportive milieu that acts against latently HIV-infected cells at various levels. To test our hypothesis, we screened six compounds on a coculture of latently infected cells (J-lat) and monocyte-derived dendritic cells (MDDCs). The protein kinase C (PKC) agonist prostratin, with a Toll-like receptor 8 (TLR8) agonist, resulted in greater reversion of HIV latency than any single compound. This combinatorial approach led to a drastic phenotypic and functional maturation of the MDDCs. Tumor necrosis factor (TNF) and cell-cell interactions were crucial for the greater reversion observed. Similarly, we found a greater potency of the combination of prostratin and TLR8 agonist in reversing HIV latency when applying it to primary cells of HIV-infected patients. Thus, we demonstrate here the synergistic interplay between TLR8-matured MDDCs and compounds acting directly on latently HIV-infected cells, targeting different mechanisms of latency, by triggering various signaling pathways. Moreover, TLR8 triggering may reverse exhaustion of HIV-specific cytotoxic T lymphocytes that might be essential for killing or constraining the latently infected cells. IMPORTANCE Curing HIV is the Holy Grail. The so-called "shock and kill" strategy relies on drug-mediated reversion of HIV latency and the subsequent death of those cells under combined antiretroviral treatment. So far, no compound achieves efficient reversal of latency or eliminates this latent reservoir. The compounds may not target all of the latency mechanisms in all latently infected cells. Moreover, HIVassociated exhaustion of the immune system hinders the efficient elimination of the reactivated cells. In this study, we demonstrated synergistic latency reversion by combining agonists for protein kinase C and Toll-like receptor 8 in a coculture of latently infected cells with myeloid dendritic cells. The drug prostratin stimulates directly the transcriptional machinery of latently infected cells, and the TLR8 agonist acts indirectly by maturing dendritic cells. These findings highlight the importance of the immune system and its activation, in combination with direct-acting compounds, to reverse latency.

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Direct Toll‐Like Receptor 8 signaling increases the functional avidity of human CD8+ T lymphocytes generated for adoptive T cell therapy strategies

Cited by 5 publications

References 43 publications

Immune Signature of Enhanced Functional Avidity CD8+ T Cells in vivo Induced by Vaccinia Vectored Vaccine

Immune Signature of Enhanced Functional Avidity CD8+ T Cells in vivo Induced by Vaccinia Vectored Vaccine

The Relevance of TLR8 in Viral Infections

Promising Role of Toll-Like Receptor 8 Agonist in Concert with Prostratin for Activation of Silent HIV

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