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Therapeutic potential of co-signaling receptor modulation in hepatitis B [RNA-Seq]

ABSTRACT: Reversing CD8+ T cell dysfunction is crucial in therapeutic approaches to eliminate chronic hepatitis B virus (HBV) infection. However, the specific molecular targets for achieving this goal are not fully understood. In this study, we conducted a comprehensive analysis of the co-signaling receptors induced during hepatocellular priming and examined the trajectory and long-term fate of dysfunctional HBV-specific CD8+ T cells. Our findings demonstrate that early during intrahepatic priming, HBV-specific CD8+ T cells selectively upregulate co-inhibitory receptors PD-1, CTLA-4, and LAG-3, as well as co-stimulatory receptors OX40, 4-1BB, and ICOS. While blocking the co-inhibitory receptors had no significant impact, activating 4-1BB and OX40, but not ICOS, transformed these cells into potent antiviral effectors. Prolonged antigenic stimulation of intrahepatically-primed dysfunctional T cells led to the development of a self-renewing, long-lived, heterogeneous population with a unique transcriptional profile that only partially overlaps with other forms of T cell hyporesponsiveness. This population consists of a dysfunctional progenitor or stem-like (TSL) population and two distinct dysfunctional tissue-resident memory (TRM) cell populations, which are hierarchically related. While 4-1BB expression is maintained across all populations, OX40 expression is limited to TSL cells. At later stages, only stimulation of 4-1BB, not OX40, conferred antiviral activity to HBV-specific CD8+ T cells. These findings highlight the therapeutic potential of co-signaling receptor modulation for chronic HBV infection and suggest that targeting all dysfunctional tissue-resident T cells, rather than solely the stem-like precursors, represents a promising strategy, distinguishing it from other conditions characterized by chronic antigenic stimulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE263460 | GEO | 2024/06/19

REPOSITORIES: GEO

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Project description:The activation of TLR-MyD88 (Toll like receptor- Myeloid differentiation factor 88) signaling within T cells functions as a potent costimulatory signal that boosts antitumor and antiviral responses. However, the molecular mechanisms underlying the costimulatory processes are poorly understood. We compared microarray gene analysis data between TLR1-TLR2 stimulated and unstimulated T cell receptor transgenic âpmelâ and MyD88-/-pmel CD8+ T cells and identified changes in the expression levels of several TNF family members. In particular, TLR-stimulation increased 4-1BB levels in pmel but not in MyD88-/-pmel T cells. A link between 4-1BB and TLR1-TLR2 signaling in CD8+ T cells was highlighted by in fact that 4-1BB-/- T cells exhibited suboptimal responses to TLR1-TLR2 agonist, but responded normally to CD28 or OX40 costimulation. Moreover, blocking 4-1BB signaling with antibodies also hindered the costimulatory effects of the TLR1-TLR2 agonist. The elevated levels of 4-1BB transcripts in TLR1-TLR2âstimulated cells were not due to increased mRNA stability nor increased histone activation but instead were associated with increased binding of p65 and c-Jun to two distinct 4-1BB promoter sites. Combining TLR1-TLR2 ligand with an agonistic anti-4-1BB antibody enhanced the antitumor activity in mice with established melanoma tumors. These studies reveal that the costimulatory effects of TLR1-TLR2 signaling in CD8+ T cells are in part mediated by 4-1BB and are important for mounting an effective antitumor immune response. CD8+ T cells from the B6.Cg-Thy1/Cy Tg(TcraTcrb)8Rest/J mice, referred to as âpmelâ T cells or from MyD88 knockout pmel mice (MyD88â/âpmel) were sorted. pmel and MyD88â/âpmel T cells were activated using MyD88â/â CD8 T cell-depleted splenocytes pulsed with 10ng/ml of mgp100. This was with or without 10Âµg/ml of Pam3CSK4. pmel or MyD88â/âpmel CD8 T cells were enriched and used for the extraction of RNA used for genomic analysis.

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Therapeutic potential of co-signaling receptor modulation in hepatitis B [RNA-Seq]

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