Sex differences in donor T cell targeting of host splenocyte subpopulations in acute and chronic murine graft-vs-host disease: results from a novel induction and assessment protocol with implications for lupus-like autoimmunity

Using the parent-into-F1 mouse model, we compared in vivo sex differences in acute graft-vs-host (GVHD) disease, a Th1- response and in chronic GVHD, a T follicular helper cell (Tfh) lupus-like antibody response. Using a novel induction protocol standardized for donor CD8 content, we analyzed both a sub-threshold and a supra-threshold dose for twenty flow cytometry outcome variables encompassing splenic subsets and T cell activation markers. A large majority (≥16) of the outcome variables identified significant differences in the two phenotypes, many with very large effect sizes. In acute GVHD, B cells exhibited the greatest degree of depletion in both sexes; however, the male response was significantly stronger. Sex differences in chronic GVHD were more widespread; females exhibited significantly greater numbers of total splenocytes and host CD4 T cells, Tfh cells, B cells and CD8 T cells consistent with greater female autoantibody production in this model. The more potent male CTL response in acute GVHD conflicts with reports of greater female CTL responses following infections or vaccines possibly reflecting the absence of exogenous innate immune stimuli in the GVHD model. To our knowledge, this study is the first to compare sex differences in splenic cellular composition and T cell activation for acute and chronic GVHD mice at 2 wk post-induction using 2 different doses of donor splenocytes standardized to CD8 T cell numbers and using an expanded number of outcome variables. The implications for lupus pathogenesis are discussed.