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Sensitivity of NK1.1-Negative NKT Cells to Transgenic BATF Defines a Role for Activator Protein-1 in the Expansion and Maturation of Immature NKT Cells in the Thymus¹

Alfred J. Zullo^*, Kamel Benlagha^2,, Albert Bendelac and Elizabeth J. Taparowsky^3,*

^* Department of Biological Sciences and Purdue Cancer Center, Purdue University, West Lafayette, IN 47907; and Department of Pathology, University of Chicago, Chicago, IL 60637

NKT cells are glycolipid-reactive lymphocytes that express markers and perform functions common to both T lymphocytes and NK cells. Although the genetic events controlling conventional T cell development are well defined, the transcription factors and genetic programs regulating NKT cell development are only beginning to be elucidated. Previously, we described the NKT cell-deficient phenotype of transgenic (Tg) mice constitutively expressing B cell-activating transcription factor (BATF), a basic leucine zipper protein and inhibitor of AP-1. In this study, we show that Tg BATF targets the majority of V14J281 (V14i⁷) NKT cells, regardless of CD4 expression and V gene usage. The residual NKT cells in the thymus of BATF-Tg mice are CD44⁺, yet are slow to display the NK1.1 marker characteristic of mature cells. As a population, BATF-expressing NKT cells are TCR/CD3^low, but express normal levels of CD69, suggesting a failure to expand appropriately following selection. Consistent with the sensitivity of NKT cells to BATF-induced changes in AP-1 activity, we detect a full complement of AP-1 basic leucine zipper proteins in wild-type NKT cells isolated from the thymus, spleen, and liver, and show that AP-1 DNA-binding activity and cytokine gene transcription are induced in NKT cells within a few hours of glycolipid Ag exposure. This study is the first to characterize AP-1 activity in NKT cells and implicates the integrity of this transcription factor complex in developmental events essential to the establishment of this unique T cell subset in the thymus.

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 Public Health Service Award CA78264 (to E.J.T.) and by a special fellowship from the Leukemia and Lymphoma Society (to K.B.). A.J.Z. was a predoctoral fellow supported by Public Health Service Award T32 GM08737 and was a recipient of a Sigma Xi Grant in Aid of Research.

² Current address: Groupe Avenir, Institut National de la Sante et de la Recherche Medicale-U561, Hopital St.-Vincent de Paul, 75014 Paris-France.

³ Address correspondence and reprint requests to Dr. Elizabeth J. Taparowsky, Department of Biological Sciences, Hansen Life Science Research Building, 201 South University Street, Purdue University, West Lafayette, IN 47907-2064. E-mail address: ejt{at}bilbo.bio.purdue.edu

⁴ Abbreviations used in this paper: -GalCer, -galacotsylceramide; BATF, B cell-activating transcription factor; bZIP, basic leucine zipper; HA, hemagglutinin; Tg, transgenic.

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