Increased Severity of Murine Lupus in Female Mice Is Due to Enhanced Expansion of Pathogenic T Cells

Abstract

A strong female predominance is a well-recognized feature of human lupus. The mechanism by which sex influences disease expression and severity is not fully understood. To address this question, we used the parent-into-F1 (p→F1) model of chronic graft-vs-host disease (cGVHD) in which lupus-like humoral autoimmunity and renal disease are induced in normal F1 mice. An advantage of this model is that the pathogenic T cells driving disease (donor strain) can be studied separately from nonspecifically activated T cells (host strain). We observed that lupus-like disease using female donor and host mice (f→F cGVHD) is characterized by more severe long-term disease (glomerulonephritis) than with male donor and host (m→M cGVHD). Interestingly, differences in disease parameters could be seen at 2 wk after parental cell transfer, as evidenced by a 2- to 3-fold greater engraftment of donor CD4+ T cells in f→F cGVHD mice, which persisted throughout disease course. Enhanced engraftment of donor CD4+ T cells in f→F cGVHD mice was not due to differences in splenic homing, alloreactive precursor frequency, initial proliferation rates, or apoptotic rates, but rather to sustained high proliferation rates during wk 2 of disease compared with m→M cGVHD mice. Crossover studies (m→F, f→M) demonstrated that enhanced donor CD4+ T cell proliferation and engraftment segregate with the sex of the host. These results demonstrate that the sex of the recipient can influence the expansion of pathogenic T cells, thus increasing long-term the burden of autoreactive T cells and resulting in greater disease severity.