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S. Matsuoka et al.
ed B6D2F1 mice were injected with 5x106 TCD-BM from WT B6 plus 1x106 T cells from either WT or MyD88-/- B6 mice, with the addition of 1x103 host-type P815 leukemia cells to the donor inoculum. All allogeneic TCD-BM recip- ients died from leukemia within two weeks after BMT, whereas leukemia mortality was significantly suppressed in the recipients of both WT and MyD88-/- T cells. While leukemia mortality was not significantly different between the allogeneic recipients of WT and MyD88-/- T cells, overall survival time was significantly prolonged in recipients of MyD88-/- T cells compared to controls, sug- gesting that MyD88 signaling in donor T cells is dispensa- ble for GvL effect and T-cell MyD88 is a therapeutic target of GvHD without GvL reduction (Figure 6A and B). To further assess GvL effects, we have performed in vivo bio- luminescent imaging (BLI) to track luciferase-transfected P815 (P815-luc) cells after BMT. Survivals were again sig- nificantly prolonged in recipients of MyD88-/- T cells com- pared to those of WT T cells (Figure 6C). Whole body BLI clearly demonstrated that growth of P815-luc cells were suppressed both in the recipients of MyD88-/- T cells and WT T cells, while P815-luc expanded vigorously in the recipients of TCD-BM alone (Figure 6D). Taken together, we concluded that GvL effects were preserved without donor T-cell MyD88 signaling.
Discussion
The expanding IL-1R/TLR superfamily now consists of more than ten TLR and IL-1R, IL-18R, and IL-33R. TLR are expressed on a wide range of myeloid cells such as macrophages and dendritic cells. However, emerging evi- dence demonstrates that TLR are also expressed on T cells.25 Signaling from TLR2, TLR3, TLR5, TLR7/8, and TLR9 has co-stimulatory role in T-cell activation, leading to enhancement of proliferation, survival, and differentia- tion towards Th1, Th17 and memory CD4+ T cells.8,25-28 TLR2 is required for expansion and differentiation of virus-specific CD8+ memory T cells.29,30 TLR4 engagement on CD4+ T cells is required for their effector functions in experimental autoimmune encephalomyelitis.9 Members of the IL-1R family including IL-1R, IL-18R, and IL-33R are also expressed in T cells and regulate various T-cell functions.7 IL-1R or IL-18R signaling in T cells is critical for Th1, Th17 and antigen-specific CD8+ T-cell responses.12,13,31 A previous study demonstrated an impaired proliferation of MyD88-deficient T cells upon antigen stimulation.12 However, in our study, prolifera- tion of WT T cells and MyD88-deficient T cells were com- parable early after allogeneic transplantation or in vitro upon CD3/CD28 stimulation, suggesting that the pres-
ABC
D
Figure 6. MyD88 signaling in donor T cells is not essential for significant graft-versus-leukemia (GvL) effects. (A and B) Lethally irradiated B6D2F1 mice were trans- planted with wild-type (WT) T-cell-depleted bone marrow cells (TCD-BM) alone (n=5) or in combination with either WT (n=11) or MyD88-/- (n=11) T cells from B6 together with 1x103 P815 leukemia cells (H-2Kd+) on day 0. Cumulative leukemia mortality (A) and overall survival (B) after bone marrow transplantation (BMT) from two experiments are combined. (C and D) Lethally irradiated B6D2F1 mice were transplanted with WT TCD-BM alone (n=10) or in combination with either WT (n=10) or MyD88-/- (n=10) T cells from B6 donors together with 5x103 P815-luc cells on day 0. Bioluminescent imaging (BLI) was performed weekly after allogeneic BMT. (C) Overall survival from two independent experiments were combined. (D) The whole body bioluminescent images from 1 of 2 similar experiments are shown.
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haematologica | 2020; 105(1)