title: 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(hi) host CD4 T cells and IL-21 expression.
abstract: 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.
authors.affiliation: Department of Pathology, 4301 Jones Bridge Road, Uniformed Services University of Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Foster
authors.forename: Mark
authors.initials: M
authors.lastname: Haas
authors.forename: Irina
authors.initials: I
authors.lastname: Puliaeva
authors.forename: Kateryna
authors.initials: K
authors.lastname: Soloviova
authors.forename: Roman
authors.initials: R
authors.lastname: Puliaev
authors.forename: Charles S
authors.initials: CS
authors.lastname: Via
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D001806:Blood Urea Nitrogen; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D002452:Cell Count; D002784:Cholesterol / Q000097:blood; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D015433:Glomerulonephritis, Membranous / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006086:Graft vs Host Disease / Q000097:blood / Q000150:complications / Q000276:immunology* / Q000473:pathology; D007074:Immunoglobulin G / Q000378:metabolism; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins / Q000235:genetics*; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008181:Lupus Nephritis / Q000175:diagnosis* / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D011507:Proteinuria / Q000175:diagnosis / Q000652:urine; D012709:Serum Albumin / Q000378:metabolism; D012727:Sex Characteristics; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D000098546:Interleukin-21
chemical_list: D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; C556694:Icos protein, mouse; D007074:Immunoglobulin G; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; D012709:Serum Albumin; D014280:Triglycerides; D002784:Cholesterol; D000098546:Interleukin-21
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