The IL-10-producing NKT10 subset plays a critical role in preventing graft-versus-host-disease

Invariant natural killer T (iNKT) cells play a role in preventing graft-versus-host disease (GVHD) in bone marrow transplantation (BMT), but it is not known whether and how the NKT10 and NKT17 subsets prevent GVHD. Here, we investigated the anti-GVH effects of iNKT cell subsets in a major-MHC mismatched murine BMT in which BALB/c recipients (H-2^d) received grafts from C57BL/6 (H-2^b) donors. The graft consisted of bone marrow and T cells from Traj18^KO (iNKT cell deficient) mice supplemented with iNKT cells purified from donors with various genetic alterations of iNKT subsets. First, NKT17-enriched CD4^- iNKT cells showed anti-GVH effects similar to those of NKT2-enriched CD4⁺ iNKT cells, while NKT2/17 deficient iNKT cells failed to prevent GVHD, suggesting that either or both of these subsets have anti-GVH function. Furthermore, IL10^KO iNKT cells completely lost their protective effects, whereas IL17AFD^KO iNKT cells demonstrated partially abrogated anti-GVH effects, supporting the indispensable role of NKT10 in preventing GVHD after BMT. Using IL-17 fate-mapping mice, we demonstrated that NKT17 can trans-differentiate into NKT10 in vitro after antigenic stimulation under T regulatory type 1 (Tr1)-promoting conditions. In conclusion, NKT10 plays a role in preventing GVHD in BMT and NKT17 may contribute to the anti-GVH effects via trans-differentiation into NKT10.