Donor CD8 T cell activation is critical for greater renal disease severity in female chronic graft-vs.-host mice and is associated with increased splenic ICOS host CD4 T cells and IL-21 expression

Lupus-like renal disease in DBA/2-into-F1 (DBA → F1) mice is driven by donor CD4 T cells and is more severe in females. Donor CD8 T cells have no known role. As expected, we observed that females receiving unfractionated DBA splenocytes (CD8 intact → F1) exhibited greater clinical and histological severities of renal disease at 13 weeks compared to males. Surprisingly, sex-based differences in renal disease severity were lost in CD8 depleted → F1 mice due to an improvement in females and a worsening in males. CD8 intact → F1 female mice exhibited significantly greater donor and host effector (CD44^hi, CD62L^lo) CD4 T cells and ICOS^hi CD4 T follicular helper cells than males. CD8 depleted → F1 female mice exhibited a reduction in the absolute numbers of host, but not donor CD4 Tfh cells and lost the significant increase in host CD4 effector cells vs. males. Greater female IL-21 expression, a product of Tfh cells, was seen in CD8 intact → F1 and although reduced was still greater than male CD8 depleted → F1 mice. Thus, donor CD8 T cells have a critical role in mediating sex-based differences in lupus renal disease severity possibly through greater host ICOS^hi CD4 T cell involvement.