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* Department of Pathology, Immunology, and Laboratory Medicine and
Department of Medicine, Division of Rheumatology and Clinical Medicine, University of Florida, Gainesville, FL 32610; and
Pathology and Laboratory Medicine Service, Malcolm Randall Veterans Affairs Medical Center, Gainesville, FL 32608
The Sle1 locus is a key determinant of lupus susceptibility in the NZM2410 mouse model. Within Sle1, we have previously shown that Sle1a expression enhances activation levels and effector functions of CD4+ T cells and reduces the size of the CD4+CD25+Foxp3+ regulatory T cell subset, leading to the production of autoreactive T cells that provide help to chromatin-specific B cells. In this study, we show that Sle1a CD4+ T cells express high levels of ICOS, which is consistent with their increased ability to help autoreactive B cells. Furthermore, Sle1a CD4+CD25+ T cells express low levels of Foxp3. Mixed bone marrow chimeras demonstrated that these phenotypes require Sle1a to be expressed in the affected CD4+ T cells. Expression of other markers generally associated with regulatory T cells (Tregs) was similar regardless of Sle1a expression in Foxp3+ cells. This result, along with in vitro and in vivo suppression studies, suggests that Sle1a controls the number of Tregs rather than their function on a per cell basis. Both in vitro and in vivo suppression assays also showed that Sle1a expression induced effector T cells to be resistant to Treg suppression, as well as dendritic cells to overproduce IL-6, which inhibits Treg suppression. Overall, these results show that Sle1a controls both Treg number and function by multiple mechanisms, directly on the Tregs themselves and indirectly through the response of effector T cells and the regulatory role of dendritic cells.
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1 This work was supported by National Institutes of Health Grants R01 AI 45050 (to L.M.) and T32 AR007603 (to C.M.).
2 Current address: Xuanwu Hospital, Capital University of Medical Science, Beijing, China.
3 Address correspondence and reprint requests to Dr. Laurence Morel, Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610-0275. E-mail address: morel{at}ufl.edu
4 Abbreviations used in this paper: Treg, regulatory T cell; DC, dendritic cell; Teff, effector T cell; BM, bone marrow; PMN, polymorphonuclear neutrophil; GITR, glucocorticoid-induced TNF receptor.
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