Contrasting Roles of the PD-1 Signaling Pathway in Dendritic Cell-Mediated Induction and Regulation of HIV-1-Specific Effector T Cell Functions

Abstract

Eliciting highly functional CD8 ϩ cytotoxic T lymphocyte (CTL) responses against a broad range of epitopes will likely be required for immunotherapeutic control of HIV-1 infection. However, the combination of CTL exhaustion and the ability of HIV-1 to rapidly establish CTL escape variants presents major hurdles toward this goal. Our previous work highlighted the use of monocyte-derived, mature, highinterleukin-12 (IL-12)-producing type 1 polarized dendritic cells (MDC1) to selectively induce more potent effector CTLs derived from naive, rather than memory, CD8 ϩ T cell precursors isolated from HIV-1-positive participants in the Multicenter AIDS Cohort Study. In this study, we report that these highly stimulatory antigen-presenting cells also express enhanced levels of the coinhibitory molecule programmed cell death ligand 1 (PD-L1), the ligand for PD-1, which is further upregulated upon subsequent stimulation with the CD4 ϩ T helper cell-derived factor CD40L. Interestingly, blocking the PD-1 signaling pathway during MDC1 induction of HIV-1-specific CTL responses inhibited the priming, activation, and differentiation of naive CD8 ϩ T cells into effector T cells expressing high levels of T-box transcription factor (T-bet hi ) and eomesodermin (Eomes ϩ ). In contrast, PD-1 blockade enhanced the overall magnitude of memory HIV-specific CTL responses and reversed the exhausted memory phenotype from a T-bet low /Eomes ϩ to a T-bet hi /Eomes ϩ phenotype. These results indicate that the PD-L1/PD-1 signaling pathway has a previously unappreciated dual role in the induction and regulation of HIV-1-specific CTL immunity, which is greatly determined by the context and differentiation stage of the responsive CD8 ϩ T cells. IMPORTANCE Targeting the PD-1/PD-L1 immune checkpoint axis with signaling inhibitors has proven to be a powerful immunotherapeutic strategy to enhance the functional quality and survival of existing antigen-specific effector T cells. However, our study demonstrates that the context and timing of PD-1 signaling in T cells greatly impact the outcome of the effector response. In particular, we show that PD-1 activation plays a positive role during the DC-mediated initiation stage of the primary T cell response, while it serves as an inhibitory mechanism during the effector phase of the response. Therefore, caution should be taken in the design of therapies that include targeting of the PD-1/PD-L1 signaling pathway in order to avoid potential negative impacts on the induction of de novo T cell responses. FIG 7 Percent of PD-1-positive CD8 ϩ and CD4 ϩ T cells during one round (12 days) of in vitro stimulation. MDC1 derived from HIV-1 ϩ participants were loaded with 18-mer HIV-1 Gag overlapping peptides and used as stimulators of T cells at a ratio of 1:10 (DC/T cells). CD8 ϩ (A) and CD4 ϩ (B) T cells were evaluated over time for PD-1 expression by flow cytometry. Results are from three separate donors.

PD-L1– and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease

“…The effect of liposomes on Tregs and IL-10 was PD-L1 dependent, while the effect of liposomes on IFN-γ anergy was not ( Figure 5C). However, PD-L1 inhibition did reduce the OVA-specific IFN-γ response to OVA 323-339 stimulation in control mice, likely due to PD-L1 tuning of DC-T cell antigen responsiveness, as previously described (44). Since both OVA-specific Tregs and IL-10 were suppressed in OVA/calcitriol liposome-and PD-L1-treated mice, the reduction in IFN-γ is more likely to be due to deletion, with unresponsive residual T cells, than regulation.…”

The PD-1/PD-L1 Axis and Virus Infections: A Delicate Balance

“…PD-1 upregulation is linked to a loss of function in HIV-specific CD8+ T cells, which can be partially reversed in vitro by a blockade of the PD-1/PD-L1 axis (Day et al, 2006; Trautmann et al, 2006). Surprisingly, the context and timing of PD-1 blockade seems to be important for its functional outcome: PD-1 signaling inhibition during stimulation of naive CD8 + T cells results in diminished activation, whereas PD-1 blockade during the T cell effector phase increases activation (Garcia-Bates et al, 2019). PD-1 blockade in rhesus macaques infected with simian immunodeficiency (SIV) rapidly increases the number and functional quality of virus-specific CD8+ T cells (Velu et al, 2009).…”

Immune Checkpoints in Viral Infections

“…The increased PD-1 expression by CD4 + T-cells is derived from the cell HIV-viral load. This expression is positively correlated with disease progression [42,125] and involved in the reduction of immune system activation that leads to the long-term survival of HIV latent reservoir T-cells [42,129]. In addition, CTLA-4 + PD-1 − memory CD4 + T-cells have also been identified as HIV-DNA latency reservoir, and the major proportion of these cells were Treg cells [130,131].…”