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Activation of natural killer T cells enhances the function of regulatory T-cell therapy in suppressing murine GVHD.

ABSTRACT: Cellular therapy with regulatory T cells (Tregs) has shown promising results for suppressing graft-versus-host disease (GVHD) while preserving graft vs tumor effects in animal models and phase 1/2 clinical trials. However, a paucity of Tregs in the peripheral blood makes it difficult to acquire sufficient numbers of cells and hampers further clinical application. Invariant natural killer T (iNKT) cells constitute another compartment of regulatory cells that ameliorate GVHD through activation of Tregs after their own activation with α-galactosylceramide (α-GalCer) or adoptive transfer. We demonstrate here that a single administration of α-GalCer liposome (α-GalCer-lipo) enhanced the in vivo expansion of Tregs after adoptive transfer in a murine GVHD model and improved therapeutic efficacy of Treg therapy even after injection of otherwise suboptimal cell numbers. Host iNKT cells rather than donor iNKT cells were required for GVHD suppression because the survival benefit of α-GalCer-lipo administration was not shown in the transplantation of cells from wild-type (WT) C57BL/6 mice into Jα18-/- iNKT cell-deficient BALB/c mice, whereas it was observed from Jα18-/- C57BL/6 donor mice into WT BALB/c recipient mice. The combination of iNKT cell activation and Treg adoptive therapy may make Treg therapy more feasible and safer by enhancing the efficacy and reducing the number of Tregs required.

SUBMITTER: Hirai T

PROVIDER: S-EPMC8238485 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Recent reports suggest that Natural Killer (NK) cells may modulate pathogenesis of primary HIV-1 infection. However, HIV dysregulates NK-cell responses. We dissected this bi-directional relationship to understand how HIV impacts NK-cell responses during primary HIV-1 infection.Paired samples from 41 high-risk, initially HIV-uninfected CAPRISA004 participants were analysed prior to HIV acquisition, and during viraemic primary HIV-1 infection. At the time of sampling post-infection five women were seronegative, 11 women were serodiscordant, and 25 women were seropositive by HIV-1 rapid immunoassay. Flow cytometry was used to measure NK and T-cell activation, NK-cell receptor expression, cytotoxic and cytokine-secretory functions, and trafficking marker expression (CCR7, ?(4)?(7)). Non-parametric statistical tests were used. Both NK cells and T-cells were significantly activated following HIV acquisition (p?=?0.03 and p<0.0001, respectively), but correlation between NK-cell and T-cell activation was uncoupled following infection (pre-infection r?=?0.68;p<0.0001; post-infection, during primary infection r?=?0.074;p?=?0.09). Nonetheless, during primary infection NK-cell and T-cell activation correlated with HIV viral load (r?=?0.32'p?=?0.04 and r?=?0.35;p?=?0.02, respectively). The frequency of Killer Immunoglobulin-like Receptor-expressing (KIR(pos)) NK cells increased following HIV acquisition (p?=?0.006), and KIR(pos) NK cells were less activated than KIR(neg) NK cells amongst individuals sampled while seronegative or serodiscordant (p?=?0.001;p<0.0001 respectively). During HIV-1 infection, cytotoxic NK cell responses evaluated after IL-2 stimulation alone, or after co-culture with 721 cells, were impaired (p?=?0.006 and p?=?0.002, respectively). However, NK-cell IFN-y secretory function was not significantly altered. The frequency of CCR7+ NK cells was elevated during primary infection, particularly at early time-points (p<0.0001).Analyses of immune cells before and after HIV infection revealed an increase in both NK-cell activation and KIR expression, but reduced cytotoxicity during acute infection. The increase in frequency of NK cells able to traffic to lymph nodes following HIV infection suggests that these cells may play a role in events in secondary lymphoid tissue.

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Activation of natural killer T cells enhances the function of regulatory T-cell therapy in suppressing murine GVHD.

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