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Hypercostimulation through 4-1BB Distorts Homeostasis of Immune Cells¹

Seung-Woo Lee^*, Shahram Salek-Ardakani^*, Robert S. Mittler and Michael Croft^2,*

^* Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and Department of Surgery and Emory Vaccine Center, University School of Medicine, Emory University, Atlanta, GA 30329

The deleterious side effects associated with a recent clinical trial with anti-CD28 superagonist Abs have questioned the use of reagents to costimulatory molecules in human therapy. We now show that sustained signaling from an agonist Ab to 4-1BB, a member of the TNFR superfamily, results in detrimental effects on immune cell homeostasis. Repeated anti-4-1BB treatment during the reconstitution of hematopoietic cells in irradiated mice engrafted with bone marrow, or in mice infected with vaccinia virus, induced abnormal apoptosis of premature and immature B cells in the bone marrow, and led to peripheral B cell depletion. Inhibition of B cell development was indirect and due to costimulation of CD8 T cells and dependent on IFN-. Moreover, anti-4-1BB also suppressed the development of NK and NKT cells, but in this case independently of T cells and IFN-. The altered NK cell homeostasis resulted from activation-induced cell death triggered by anti-4-1BB. These results show that hypercostimulation elicits strong T cell immunity, but it can simultaneously distort immune homeostasis, suggesting that careful attention to activity, dose, and periodicity of treatment will be needed in any immunotherapeutic strategy with agonist Abs to costimulatory molecules.

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 by National Institutes of Health Grants AI42944 and AI067341 (to M.C.) and a fellowship from the Diabetes and Immune Disease National Research Institute (to S.-W.L.). This is manuscript No. 1023 from the La Jolla Institute for Allergy and Immunology.

² Address correspondence and reprint requests Dr. Michael Croft, Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: mick{at}liai.org

³ Abbreviations used in this paper: 4-1BBL, 4-1BB ligand; BM, bone marrow; LN, lymph node; DC, dendritic cell; VACV, vaccinia virus; GC, germinal center; iNKT, invariant NKT; wt, wild type.