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2015 ; 74
(4
): 778-85
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Dysregulated CD4+ T cells from SLE-susceptible mice are sufficient to accelerate
atherosclerosis in LDLr-/- mice
#MMPMID24395554
Wilhelm AJ
; Rhoads JP
; Wade NS
; Major AS
Ann Rheum Dis
2015[Apr]; 74
(4
): 778-85
PMID24395554
show ga
OBJECTIVE: Accelerated atherosclerosis is a major source of morbidity in systemic
lupus erythematosus (SLE). However, the cause of SLE-accelerated atherosclerosis
remains unclear. METHODS: CD4(+) T cells from C57/Bl/6 (B6) or SLE-susceptible
B6.Sle1.2.3 (B6.SLE) mice were transferred into LDLr(-/-), Rag(-/-) mice. T cells
were examined for cytokine production and expression of interleukin-10 receptor
(IL-10R) and functional markers. T cells were isolated based on FoxP3(GFP)
expression and transferred to LDLr(-/-), Rag(-/-) mice to establish a role for
B6.SLE effector T cells (Teff) in atherosclerosis. RESULTS: Mice receiving whole
B6.SLE CD4(+) T cells displayed no other SLE phenotype; however, atherosclerosis
was increased nearly 40%. We noted dysregulated IL-17 production and reduced
frequency of IL-10R expression by B6.SLE regulatory T cells (Treg). Functional
assays indicated resistance of B6.SLE Teff to suppression by both B6.SLE and B6
Treg. Transfer experiments with CD4(+)FoxP3(-) Teff and CD4(+)FoxP3(+) Treg from
B6.SLE and B6 mice, respectively, resulted in increased atherosclerosis compared
with B6 Teff and Treg recipients. Treg isolated from mice receiving B6.SLE Teff
with B6 Treg had increased production of IL-17 and fewer expressed IL-10R
compared with B6 Teff and Treg transfer. CONCLUSIONS: Transfer of B6.SLE Teff to
LDLr(-/-), Rag(-/-) mice results in accelerated atherosclerosis independent of
the source of Treg. In addition, the presence of B6.SLE Teff resulted in more
IL-17-producing Treg and fewer expressing IL-10R, suggesting that B6.SLE Teff may
mediate phenotypic changes in Treg. To our knowledge, this is the first study to
provide direct evidence of the role of B6.SLE Teff in accelerating
atherosclerosis through resistance to Treg suppression.
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