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.
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.
Foster
Anthony D
AD
Department of Pathology, 4301 Jones Bridge Road, Uniformed Services University of Health Sciences, Bethesda, MD 20814, USA.
Haas
Mark
M
Puliaeva
Irina
I
Soloviova
Kateryna
K
Puliaev
Roman
R
Via
Charles S
CS
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
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
J Clin Invest. 1996 Aug 1;98(3):826-37
8698875
J Exp Med. 1983 Feb 1;157(2):755-71
6218218
Clin Immunol Immunopathol. 1990 Nov;57(2):263-73
2208807
Annu Rev Immunol. 1994;12:487-520
8011289
J Exp Med. 1983 Aug 1;158(2):546-58
6224882
J Immunol. 1987 Sep 15;139(6):1840-9
2957440
Kidney Int. 1998 Feb;53(2):320-30
9461092
J Immunol. 1989 Jul 1;143(1):103-12
2525144
J Immunol. 2005 Jun 15;174(12):7600-9
15944260
Immunity. 2008 Jul 18;29(1):138-49
18599325
Semin Immunol. 1994 Feb;6(1):49-54
8167307
Proc Natl Acad Sci U S A. 1987 Dec;84(24):9150-4
3480535
J Clin Invest. 1988 Nov;82(5):1676-84
3183062
J Immunol. 2005 Apr 15;174(8):5100-9
15814741
J Immunol. 2003 Dec 1;171(11):5795-801
14634088
J Clin Invest. 2000 Sep;106(6):R39-47
10995792
Clin Exp Immunol. 1990 Dec;82(3):527-32
2148286
J Clin Invest. 1993 Apr;91(4):1687-96
8473512
J Immunol. 2007 Mar 15;178(6):3822-30
17339481
Autoimmun Rev. 2009 Jan;8(3):219-23
18725326
J Immunol. 1988 Nov 15;141(10):3370-6
3263424
Trends Immunol. 2006 Jun;27(6):261-7
16684621
J Immunol. 2007 Nov 1;179(9):5886-96
17947662
J Invest Dermatol. 1985 Jul;85(1 Suppl):115s-120s
3159804
J Immunol. 1984 Apr;132(4):1814-20
6321591
J Immunol. 1993 Jan 15;150(2):361-6
8419469
Immunol Today. 1988 Jul-Aug;9(7-8):207-13
3076417
Clin Exp Immunol. 1993 Mar;91(3):442-8
8443966
Exp Mol Pathol. 2005 Oct;79(2):136-45
15979610
J Immunol. 1981 Dec;127(6):2435-8
6975323
J Exp Med. 1982 May 1;155(5):1555-60
6978376
J Immunol. 2007 Dec 15;179(12):8180-90
18056361
Nature. 2005 May 26;435(7041):452-8
15917799
Nat Rev Immunol. 2001 Nov;1(2):147-53
11905822
J Immunol. 2007 Jan 1;178(1):95-102
17182544
J Exp Med. 1993 May 1;177(5):1367-81
8478612
J Exp Med. 2008 Nov 24;205(12):2873-86
18981236
J Immunol. 1983 Jun;130(6):2693-701
6602176
Nature. 1987 Aug 27-Sep 2;328(6133):805-11
3498121
J Immunol. 1983 Jan;130(1):209-15
6183348
J Exp Med. 1988 May 1;167(5):1713-8
3259258
J Exp Med. 1990 Feb 1;171(2):503-17
2303783
Curr Dir Autoimmun. 2003;6:228-44
12408055
J Immunol. 2008 Jul 1;181(1):47-61
18566369
J Exp Med. 1990 Jan 1;171(1):265-92
2104919
J Immunol. 2004 Jul 1;173(1):68-78
15210760
J Exp Med. 1994 Apr 1;179(4):1137-43
7908320
J Immunol. 2008 Nov 1;181(9):5912-29
18941180
Arthritis Rheum. 1990 Aug;33(8):1216-25
1975176