Reduced expression of decay-accelerating factor 1 on CD4+ T cells in murine systemic autoimmune disease.
OBJECTIVE
Deficiency of decay-accelerating factor 1 (termed Daf1 in mice) has been shown to exacerbate autoimmunity, and recent studies have suggested that this may be explained by Daf1 acting as a regulator of T cell immunity. The aim of this study was to determine whether Daf1 expression on T cells is modulated during development of autoimmunity in mice.


METHODS
To test this hypothesis, we examined Daf1 levels in NZB, DBA/2, and B10.S mice before and after induction of murine mercury-induced autoimmunity (mHgIA). Daf1 was measured by real-time polymerase chain reaction and flow cytometry, and levels of Daf1 were correlated with markers of lymphocyte activation and cytokine production.


RESULTS
Autoimmune-prone NZB mice had low endogenous levels of Daf1 irrespective of the induction of mHgIA. Induction of autoimmunity reduced Daf1 expression in mHgIA-sensitive B10.S mice, particularly on activated/memory (CD44(high)) CD4+ T cells that accumulate as a result of exposure to mercury. Murine mercury-induced autoimmunity-resistant DBA/2 mice, which fail to accumulate CD44(high) T cells, showed no change in Daf1 expression. Modulation of Daf1 expression was found to require CD4+ T cell costimulation, since B10.S mice deficient in CD28 were unable to down-regulate Daf1 or accumulate activated/memory CD4+ T cells. In B10.S mice exposed to mercury, the production of interleukin-4 (IL-4), but not that of IL-2 or interferon-gamma, in the spleen was associated with CD44(high),Daf1(low),CD4+ T cells.


CONCLUSIONS
These findings demonstrate that reduction of Daf1 expression is closely associated with CD4+ T cell activation and the accumulation of CD44(high)(activated/memory),CD4+ T cells in both spontaneous and induced systemic autoimmune disease.
Cauvi
David M
DM
W. M. Keck Autoimmune Disease Center, The Scripps Research Institute, La Jolla, California, USA.
Cauvi
Gabrielle
G
Pollard
K Michael
KM
D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D015551:Autoimmunity / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008628:Mercury; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D018958:CD55 Antigens; D018960:Hyaluronan Receptors; D012333:RNA, Messenger; C521184:decay-accelerating factor 1, mouse; D015847:Interleukin-4; D008628:Mercury