title: Donor CD8 T cells and IFN-gamma are critical for sex-based differences in donor CD4 T cell engraftment and lupus-like phenotype in short-term chronic graft-versus-host disease mice.
abstract: The transfer of unfractionated DBA/2J (DBA) splenocytes into B6D2F(1) (DBA → F(1)) mice results in greater donor CD4 T cell engraftment in females at day 14 that persists long-term and mediates greater female lupus-like renal disease. Although donor CD8 T cells have no demonstrated role in lupus pathogenesis in this model, we recently observed that depletion of donor CD8 T cells prior to transfer eliminates sex-based differences in renal disease long-term. In this study, we demonstrate that greater day 14 female donor CD4 engraftment is also critically dependent on donor CD8 T cells. Male DBA → F(1) mice exhibit stronger CD8-dependent day 8-10 graft-versus-host (GVH) and counter-regulatory host-versus-graft (HVG) responses, followed by stronger homeostatic contraction (days 10-12). The weaker day 10-12 GVH and HVG in females are followed by persistent donor T cell activation and increasing proliferation, expansion, and cytokine production from days 12 to 14. Lastly, greater female day 14 donor T cell engraftment, activation, and cytokine production were lost with in vivo IFN-γ neutralization from days 6 to 14. We conclude the following: 1) donor CD8 T cells enhance day 10 proliferation of donor CD4 T cells in both sexes; and 2) a weaker GVH/HVG in females allows prolonged survival of donor CD4 and CD8 T cells, allowing persistent activation. These results support the novel conclusion that sex-based differences in suboptimal donor CD8 CTL activation are critical for shaping sex-based differences in donor CD4 T cell engraftment at 2 wk and lupus-like disease long-term.
authors.affiliation: Department of Pathology, Uniformed Services University of Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Foster
authors.forename: Kateryna
authors.initials: K
authors.lastname: Soloviova
authors.forename: Irina
authors.initials: I
authors.lastname: Puliaeva
authors.forename: Maksym
authors.initials: M
authors.lastname: Puliaiev
authors.forename: Roman
authors.initials: R
authors.lastname: Puliaev
authors.forename: Fred
authors.initials: F
authors.lastname: Finkelman
authors.forename: Charles S
authors.initials: CS
authors.lastname: Via
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D017690:Cell Transplantation / Q000009:adverse effects / Q000379:methods; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D006789:Host vs Graft Reaction / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D013997:Time Factors
chemical_list: D016207:Cytokines; D007371:Interferon-gamma