Donor CD8 T cell activation is critical for sex based differences in lupus-like disease in DBA-into-F1 mice. (93.31)

Abstract Transfer of DBA splenocytes into BDF1 mice (DBA->F1) results in donor CD4 T cell mediated lupus-like renal disease that is more severe in females and preceded at day 14 by greater female CD4 T cell engraftment. Donor CD8 T cells have no reported role. To compare sex based differences in donor CD4 T cell function, we transferred CD8 depleted DBA splenocytes and surprisingly observed that greater female renal disease severity and greater day 14 female CD4 engraftment were lost or significantly reduced. Kinetic analyses demonstrated that mice receiving undepleted donor cells exhibited a stronger day 8-12 graft-vs.-host (GVH) and host vs. graft (HVG) responses in males followed by contraction of donor CD8 T cells. The weaker GVH/HVG in females was followed by persistence/increase in donor CD8 T cells. Importantly, sex based differences in GVH/HVG were lost or attenuated in mice receiving CD8 depleted splenocytes, linking sex based differences in day 8-10 GVH/HVG to differences in day 14 CD4 engraftment. We conclude that: 1) donor CD8 T cells enhance the proliferation of donor CD4 T cells in both sexes; and 2) prolonged survival of donor CD8 T cells in females is causally related to greater day 14 engraftment of donor CD4 T cells in females. These results support the novel conclusion that sex based differences in sub optimal donor CD8 CTL activation are critical for shaping sex based differences in donor CD4 T cell engraftment at two weeks and lupus like disease long term.