A radio-resistant perforin-expressing lymphoid population controls allogeneic T cell engraftment, activation and onset of GVHD in mice
- Author(s)
- Davis, JE; Harvey, M; Gherardin, NA; Koldej, R; Huntington, N; Neeson, P; Trapani, JA; Ritchie, DS;
- Details
- Publication Year 2014-11-12,Volume 21,Issue #2,Page 242-9
- Journal Title
- Biol Blood Marrow Transplant
- Publication Type
- Journal Article
- Abstract
- Immunosuppressive pre-transplantation conditioning is essential for donor cell engraftment in allogeneic BMT. The role of residual post-conditioning recipient immunity in determining engraftment is poorly understood. We examined the role of recipient perforin in the kinetics of donor cell engraftment. MHC-mismatched BMT mouse models demonstrated that both the rate and proportion of donor lymphoid cell engraftment, and expansion of effector memory donor T cells in both spleen and BM were significantly increased within 5-7 days post BMT in perforin-deficient (pfn-/-) recipients, compared with wild-type (WT). In WT recipients, depletion of natural killer (NK) cells prior to BMT enhanced donor lymphoid cell engraftment to that seen in pfn-/- recipients. This demonstrated that a perforin-dependent, NK-mediated, host-versus-graft (HVG) effect limits the rate of donor engraftment and T cell activation. Radiation-resistant NKT cells survived in the BM of lethally irradiated mice and may drive NK cell activation, resulting in the HVG effect. Furthermore, reduced pre-transplant irradiation doses in pfn-/- recipients permitted long-term donor lymphoid cell engraftment. These findings suggest that suppression of perforin activity or selective depletion of recipient NK cells prior to BMT could be utilized to improve donor stem cell engraftment in turn allowing for the reduction of pre-transplant conditioning.
- Publisher
- Elsevier
- Research Division(s)
- Molecular Immunology
- Publisher's Version
- https://doi.org/10.1016/j.bbmt.2014.11.003
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-01-22 02:19:20
Last Modified: 2015-01-22 02:26:48