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* Dermatology Branch and
Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, MD 20814; and
Department of Immunology, Akita Unversity School of Medicine, Akita City, Japan
To elucidate the mechanisms controlling peripheral tolerance, we established two transgenic (Tg) mouse strains expressing different levels of membrane-bound OVA (mOVA) as a skin-associated self-Ag. When we transferred autoreactive TCR-Tg CD8 T cells (OT-I cells), keratin 14 (K14)-mOVAhigh Tg mice developed autoreactive skin disease (graft-vs-host disease (GVHD)-like skin lesions) while K14-mOVAlow Tg mice did not. OT-I cells in K14-mOVAhigh Tg mice were fully activated with full development of effector function. In contrast, OT-I cells in K14-mOVAlow Tg mice proliferated but did not gain effector function. Exogenous IL-15 altered the functional status of OT-I cells and concomitantly induced disease in K14-mOVAlow Tg mice. Conversely, neutralization of endogenous IL-15 activity in K14-mOVAhigh Tg mice attenuated GVHD-like skin lesions induced by OT-I cell transfer. Futhermore, K14-mOVAhigh Tg mice on IL-15 knockout or IL-15R
knockout backgrounds did not develop skin lesions after adoptive transfer of OT-I cells. These results identify IL-15 as an indispensable costimulator that can determine the functional fate of autoreactive CD8 T cells and whether immunity or tolerance ensues, and they suggest that inhibition of IL-15 function may be efficacious in blocking expression of autoimmunity where a breach in peripheral tolerance is suspected.
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1 This work was supported by intramural research funds of the Center for Cancer Research, National Cancer Institute/National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Stephen I. Katz, Building 31/Room 4C32, National Institutes of Health, Bethesda, MD 20892. E-mail address: katzs{at}od.niams.nih.gov
3 Abbreviations used in this paper: DC, dendritic cell; 
c, common -chain; GVHD, graft-vs-host disease; HA, hemagglutinin; K14, keratin 14; KO, knockout; LC, Langerhans cell; LN, lymph node; MFI, mean fluorescence intensity; mOVA, membrane-bound OVA; Tg, transgenic; TNCB, trinitrochlorobenzene.
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