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* Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and
Department of Electrical Engineering, University of Texas at Dallas, Richardson, TX 75080
The development of approaches for Ag delivery to the appropriate subcellular compartments of APCs and the optimization of Ag persistence are both of central relevance for the induction of protective immunity or tolerance. The expression of the neonatal Fc receptor, FcRn, in APCs and its localization to the endosomal system suggest that it might serve as a target for Ag delivery using engineered Fc fragment-epitope fusions. The impact of FcRn binding characteristics of an Fc fragment on in vivo persistence allows this property to also be modulated. We have therefore generated recombinant Fc (mouse IgG1-derived) fusions containing the N-terminal epitope of myelin basic protein that is associated with experimental autoimmune encephalomyelitis in H-2u mice. The Fc fragments have distinct binding properties for FcRn that result in differences in intracellular trafficking and in vivo half-lives, allowing the impact of these characteristics on CD4+ T cell responses to be evaluated. To dissect the relative roles of FcRn and the "classical" Fc
Rs in Ag delivery, analogous aglycosylated Fc-MBP fusions have been generated. We show that engineered Fc fragments with increased affinities for FcRn at pH 6.0–7.4 are more effective in delivering Ag to FcRn-expressing APCs in vitro relative to their lower affinity counterparts. However, higher affinity of the FcRn-Fc interaction at near neutral pH results in decreased in vivo persistence. The trade-off between improved FcRn targeting efficiency and lower half-life becomes apparent during analyses of T cell proliferative responses in mice, particularly when Fc-MBP fusions with both FcRn and FcR binding activity are used.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by grants from the National Multiple Sclerosis Society (RG 2411) and the National Institutes of Health (AI/NS ROI 42949).
2 Address correspondence and reprint requests to Dr. E. Sally Ward, Department of Immunology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9093. E-mail address: Sally.Ward{at}UTsouthwestern.edu
3 Abbreviations used in this paper: FcRn, neonatal Fc receptor; Abdegs, Abs that enhance IgG degradation; β2m, β2-microglobulin; CHO, Chinese hamster ovary; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; mDC, myeloid dendritic cell; tg, transgenic; WT, wild type.
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