Host Foxp3+CD4+ Regulatory T Cells Act as a Negative Regulator of Dendritic Cells in the Peritransplantation Period

Abstract

Host Foxp3+CD4+ regulatory T cells (Tregs) have been shown to suppress graft-versus-host disease (GVHD) in experimental bone marrow transplantation (BMT) models; however, the detailed mechanism is unknown. To address this issue, we established a murine MHC-haploidentical BMT model (BDF1 (H-2b/d) → B6C3F1 (H-2b/k)), in which transplantation following conditioning with high-dose (13 Gy) or low-dose (5 Gy) total body irradiation corresponds to myeloablative stem cell transplantation (MAST) or reduced-intensity stem cell transplantation (RIST) BMT. All MAST recipients died of GVHD within 70 d, whereas RIST recipients developed almost no GVHD and survived for at least 3 mo. In this BMT model, we investigated the kinetics of immune cells in the mesenteric lymph nodes because GVHD was most prominent in the intestines. Host Tregs that survived after total body irradiation could proliferate transiently by day 4. Comparing the kinetics of immune cells among MAST, RIST, and anti-CD25 mAb-treated RIST, we found that the transiently surviving host Tregs were fully functional, closely contacted with host dendritic cells (DCs), and significantly restrained the maturation (CD80 and CD86 expression) of DCs in a dose-dependent manner. There was a positive correlation between the ratio of DCs to host Tregs and the extent of maturation of DCs. Host Tregs suppressed alloresponse mainly by contact inhibition. Host Tregs are already active in lymph nodes before transplantation and restrain the maturation of host DCs, thereby dampening the ability of DCs to activate allogeneic donor T cells and consequently reducing the magnitude of graft-versus-host reaction. Thus, host Tregs are negative regulators of host DCs that act in the peritransplantation period.

TIGIT+ iTregs elicited by human regulatory macrophages control T cell immunity

“…We imagine that miTregs could contribute to long-term acceptance of allografts in two ways. First, direct iTregs could facilitate indirect nTreg responses, perhaps by modifying recipient DC 68 , 69 to initiate a feed-forward loop of ‘infectious tolerance’ 70 . Notably, immature mo-DCs exposed to Mreg-cocultured T cells were relatively refractory to maturation with TNFα.…”

STAT6 and Furin Are Successive Triggers for the Production of TGF-β by T Cells

“…However, in STAT6 –/– BMT recipients, both numbers remained low. The number of recipient Tregs – which regulate GVHD during the early days after BMT(41) – likewise remained low in Hpb -infected STAT6 –/– recipients (Figure 6 and 7). Add-back of TGFβ to STAT6 –/– T cell cultures restored the generation of Tregs (Supplemental Figure 2), as described previously(42).…”

Helminth-Induced Production of TGF-β and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells

“…Foxp3 + Tregs of recipient (host) or donor origin (4, 51, 52) suppress GVHD and helminths promote the expansion of Tregs. Therefore, we investigated whether host iNKT cells are necessary for helminth-induced expansion of Tregs.…”