Mechanisms of Predominance of the Natural Killer T subset after In Vivo Irradiation and Impact on Bone Marrow Transplantation

Abstract

The minor subset of natural killer (NK) T cells becomes predominant among all T cells in the spleen after fractionated irradiation of lymphoid tissues (total lymphoid irradiation; TLI). It is not clear whether the predominance is due to radioresistance and /or to rapid renewal of NKT cells from progenitors, and whether predominance occurs after single doses of total body irradiation (TBI). The current study shows that predominance gradually emerges after increasing single doses of TBI due to differences in radioresistance of NKT cells versus non-NKT cells. Radioresistance is linked to high levels of expression of the intracellular anti-apoptotic molecule, Bcl-2, but not Bcl-xL. Transgenic over-expression of Bcl-2 in all T cells prevented predominance. GVHD was more severe after bone marrow transplantation in NKT cell deficient Jα18−/− hosts than in wild type hosts conditioned with TBI or TLI. The residual NKT cells were 10 fold more abundant in the wild type spleen after TLI versus TBI. In conclusion, differences in resistance of T cell subsets to radiation induced apoptosis results in a marked alteration in the balance of T cell subsets favoring NKT cells that regulate GVHD after bone marrow transplantation.