HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cen, O. Articles by Stein, P. L. Search for Related Content PubMed PubMed Citation Articles by Cen, O. Articles by Stein, P. L.

The Adaptor Molecule Signaling Lymphocytic Activation Molecule-Associated Protein (SAP) Regulates IFN- and IL-4 Production in V14 Transgenic NKT Cells via Effects on GATA-3 and T-bet Expression¹

Osman Cen^*, Aki Ueda^*, Laura Guzman^*, Jimmy Jain^*, Hamid Bassiri^,, Kim E. Nichols^, and Paul L. Stein^2,*

^* Department of Dermatology, Northwestern University, Chicago, IL 60611; and Department of Pediatrics, Infectious Diseases Fellowship Training Program, and Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104

NKT cells comprise a rare regulatory T cell population of limited TCR diversity, with most cells using a V14J18 TCR. These cells exhibit a critical dependence on the signaling adapter molecule, signaling lymphocytic activation molecule-associated protein (SAP), for their ontogeny, an aspect not seen in conventional β T cells. Prior studies demonstrate that SAP enhances TCR-induced activation of NF-B in CD4⁺ T cells. Because NF-B is required for NKT cell development, SAP might promote the ontogeny of this lineage by signaling to NF-B. In this study, we demonstrate that forced expression of the NF-B target gene, Bcl-x_L, or inhibitory NF-B kinase β, a catalytic subunit of the IB kinase complex essential for NF-B activation, fails to restore NKT cell development in sap^–/– mice, suggesting that SAP mediates NKT cell development independently of NF-B. To examine the role of SAP in NKT cell function, we generated NKT cells in sap^–/– mice by expressing a transgene encoding the V14J18 component of the invariant TCR. These cells bound -galactosylceramide-loaded CD1d tetramers, but exhibited a very immature CD24⁺NK1.1^– phenotype. Although sap^–/– tetramer-reactive cells proliferated in response to TCR activation, they did not produce appreciable levels of IL-4 or IFN-. The reduction in cytokine production correlated with the near absence of GATA-3 and T-bet, key transcription factors regulating cytokine expression and maturation of NKT cells. Ectopic expression of GATA-3 partially restored IL-4 production by the NKT cells. Collectively, these data suggest that by promoting GATA-3 and T-bet expression, SAP exerts control over NKT cell development and mature NKT cell cytokine production.

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 grants from the National Institutes of Health (to K.E.N. and P.L.S.), American Heart Association (to P.L.S.), and XLP Research Trust (to K.E.N.).

² Address correspondence and reprint requests to Paul Stein, Department of Dermatology, Ward 9-003, 303 East Chicago Avenue, Chicago, IL 60611. E-mail address: p-stein2{at}northwestern.edu

³ Abbreviations used in this paper: DP, double positive; -GalCer, -galactosylceramide; HSA (CD24), heat stable Ag; HSCP, hematopoietic stem cell progenitor; IKKβ, inhibitory NF-B kinase β; SAP, signaling lymphocytic activation molecule-associated protein; SLAM, signaling lymphocytic activation molecule; Tg, transgenic; wt, wild type; XLP, X-linked lymphoproliferative disease.