Increased Expression of TLR7 in CD8⁺T Cells Leads to TLR7-Mediated Activation and Accessory Cell-Dependent IFN-γ Production in HIV Type 1 Infection

Abstract

It has recently been demonstrated that toll-like receptors (TLRs) can recognize structural conserved motifs carried by circulating microbial products and lead to systemic immune responses in individuals infected with HIV-1. TLRs have been detected in CD8(+) T cells at either a protein or RNA level. The role of TLRs on CD8(+) T cells involved in the host's immune responses during HIV-1 infection has not been well characterized. In this study, we analyzed expression of TLR4, TLR5, TLR7, and TLR8 in CD8(+) T cells in HIV-1 infection. All these four TLRs could be detected in CD8(+) T cells, but only TLR7 in CD8(+) T cells from HIV-1-infected individuals showed a higher expression level compared with that from healthy individuals (p < 0.05). The function of TLR7 in CD8(+) T cells was then investigated. We found that TLR7 ligand responsiveness significantly increased the expression of immune activation markers on purified CD8(+) T cells in HIV-1-infected individuals compared with healthy controls. And the levels of these markers were equivalent to those achieved by CD8(+) T cells from peripheral blood mononuclear cells (PBMCs). However, we also observed that TLR7 ligand stimulated significant IFN-gamma production by CD8(+) T cells in an accessory cell-dependent manner. Therefore, although CD8(+) T cells can be directly activated by TLR7, accessory cells must play an essential role in the activation of effective functions such as IFN-gamma production. These findings suggest that the abnormal expression of TLR7 in CD8(+) T cells from HIV-1-infected individuals may contribute to the abnormal immune activation in HIV-1 infection and play an important role in HIV-1 pathogenesis.

Insights into the role of Toll-like receptors in modulation of T cell responses

“…Lack of response to LPS may be associated with the absence of CD14 expression by these cells. However, there is the suggestion that TLR4 can sense its ligands even in the absence of CD14 (Song et al 2009). Similar response that included proliferation and IL-2 production by CD4+ T cells after treatment with TLR2, 5 and 7 agonists was also observed in a subsequent study (Caron et al 2005).…”

“…In HIV infection, TLR-costimulation in T cells also seems to play an important role. For example, Song and colleagues found a marked increase in TLR7 protein expression in CD8+ T cells isolated from HIV patients (Song et al 2009). Interestingly, direct stimulation of CD8+ T cells from HIV patients with a TLR7 ligand (CL097) led to increased activation, proliferation and IFN-γ production of CD8+ T cells suggesting that TLR7-costimulation in CD8+ T cells may play a beneficial role in HIV-infected individuals.…”

TLR7 Agonist GS-9620 Is a Potent Inhibitor of Acute HIV-1 Infection in Human Peripheral Blood Mononuclear Cells

“…TLR7 is highly expressed in plasmacytoid dendritic cells (pDCs) (3–5) but is also found to a lower extent on other leukocyte subpopulations, including monocytes (6), B cells (7), CD4 + T cells (8–10), and CD8 + T cells (8, 11, 12). Ligand binding to TLR7 results in activation of this receptor, recruitment of the cytoplasmic adaptor protein MyD88, and activation of the transcription factors nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and interferon regulatory factor 7 (IRF7).…”

R-848 triggers the expression of TLR7/8 and suppresses HIV replication in monocytes

“…TLR3, 7, 8, and 9 are implicated in anti-viral defense [5,8]. A recent study reported that TLR7/8 can recognize uridine-rich ssRNA (ssRNA40) derived from the HIV-1 long terminal repeat (LTR) [9], suggesting that TLR7/8 may be involved in HIV infection as other investigators have previously reported [10,11]. …”