T cell TRAIL promotes murine lupus by sustaining effector CD4 Th cell numbers and by inhibiting CD8 CTL activity.
T cells play an essential role in driving humoral autoimmunity in lupus. Molecules such as TRAIL exhibit strong T cell modulatory effects and are up-regulated in lupus, raising the possibility that they may influence disease severity. To address this possibility, we examined the role of TRAIL expression on pathogenic T cells in an induced model of murine lupus, the parent-into-F(1) (P-->F(1)) model of chronic graft-vs-host disease (GVHD), using wild-type or TRAIL-deficient donor T cells. Results were compared with mice undergoing suppressive acute GVHD. Although chronic GVHD mice exhibited less donor T cell TRAIL up-regulation and IFN-alpha-inducible gene expression than acute GVHD mice, donor CD4(+) T cell TRAIL expression in chronic GVHD was essential for sustaining effector CD4(+) Th cell numbers, for sustaining help to B cells, and for more severe lupus-like renal disease development. Conversely, TRAIL expression on donor CD8(+) T cells had a milder, but significant down-regulatory effect on CTL effector function, affecting the perforin/granzyme pathway and not the Fas ligand pathway. These results indicate that, in this model, T cell-expressed TRAIL exacerbates lupus by the following: 1) positively regulating CD4(+) Th cell numbers, thereby sustaining T cell help for B cells, and 2) to a lesser degree by negatively regulating perforin-mediated CD8(+) CTL killing that could potentially eliminate activated autoreactive B cells.
Rus
Violeta
V
Research Service, Department of Veterans Affairs Medical Center, Baltimore, MD 21201, USA. vrus@umaryland.edu
Nguyen
Vinh
V
Puliaev
Roman
R
Puliaeva
Irina
I
Zernetkina
Valentina
V
Luzina
Irina
I
Papadimitriou
John C
JC
Via
Charles S
CS
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053804:Granzymes / Q000276:immunology / Q000378:metabolism; D007111:Immunity, Cellular / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000276:immunology / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000172:deficiency / Q000276:immunology*
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D054353:Perforin; D053804:Granzymes