Host Natural Killer T Cells Regulate Allogeneic Donor CD8⁺ T Cell Expression of Homing and Chemokine Receptors and Tissue Migration

Natural killer T (NKT) cells recognize CD1d, and include invariant Jα18⁺ iNKT and non-invariant subpopulations. NKT prevent graft versus host disease (GVHD) via IL-4, but the mechanisms remain unclear. We have reported that donor CD8⁺ T cells are confined to host lympho-hematological tissues in anti-CD3-conditioned recipients, and the confinement is associated with presence of high percentage of residual host NKT. But it is unknown whether NKT can regulate T cell migration. In the current studies, using NKT deficient CD1d^-/-, Rag-2^-/-, and iNKT deficient Jα18^-/- host-type mice, and by add-back of iNKT cells from wild-type or IL-4^-/- host-type mice to in vivo transplantation and/or in vitro co-culture experiments, we observed that 1)host NKT down-regulate donor CD8⁺ T expression of α4β7, CCR5, CCR6, CXCR3 but upregulate expression of CCR3, as well as down-regulate GVHD target tissue expression of ccl3-5 and Cxcl9-11 chemokines in an IL-4 dependent manner. 2) iNKT and non-invariant NKT have redundant role in regulating donor T expression of chemokine receptors; but iNKT are required for down-regulating tissue release of chemokines. 3) iNKT down-regulate donor CD8⁺ T expression of α4β7 without reduction of IFN-g production. These indicate that NKT preventing GVHD can be via reducing donor T tissue migration capacity. (This work was supported by Nesvig Lymphoma foundation)