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

• Published in: Clinical immunology (Orlando, Fla.) Fla.), 2010-07, Vol.136 (1), p.61-73
• Main Authors: Foster, Anthony D, Haas, Mark, Puliaeva, Irina, Soloviova, Kateryna, Puliaev, Roman, Via, Charles S
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Antinuclear - blood; Antigens, CD - metabolism; Antigens, Differentiation, T-Lymphocyte - metabolism; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; Blood Urea Nitrogen; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - transplantation; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - transplantation; Cell Count; Cholesterol - blood; Female; Gene Expression - genetics; Gene Expression - immunology; Glomerulonephritis, Membranous - etiology; Glomerulonephritis, Membranous - immunology; Glomerulonephritis, Membranous - metabolism; Glomerulonephritis, Membranous - pathology; Graft vs Host Disease - blood; Graft vs Host Disease - complications; Graft vs Host Disease - immunology; Graft vs Host Disease - pathology; Immunoglobulin G - metabolism; Inducible T-Cell Co-Stimulator Protein; Interleukins - genetics; Kidney - metabolism; Kidney - pathology; Kidney - ultrastructure; Lupus Nephritis - diagnosis; Lupus Nephritis - etiology; Lupus Nephritis - immunology; Lupus Nephritis - metabolism; Lupus Nephritis - pathology; Lymphocyte Depletion; Male; Mice; Mice, Inbred DBA; Mice, Inbred Strains; Proteinuria - diagnosis; Proteinuria - urine; Serum Albumin - metabolism; Sex Characteristics; Spleen - cytology; Spleen - immunology; Spleen - metabolism; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - transplantation; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Helper-Inducer - metabolism; Triglycerides - blood
• ISSN: 1521-7035
• DOI: 10.1016/j.clim.2010.01.005

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.