| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
* Section of Cell and Molecular Biology, Institute of Cancer Research, London, United Kingdom; and
Tumour Immunology Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, United Kingdom
The transcription factors mediating the development of CD1d-restricted invariant NKT (iNKT) cells remain incompletely described. Here, we show that loss of the AP-1 transcription factor Fra-2 causes a marked increase in the number of both thymic and peripheral iNKT cells, without affecting the development of other T-lineage cells. The defect is cell-autonomous and is evident in the earliest iNKT precursors. We find that iNKT cells expressing the lower affinity TCRVβ8 are proportionally overrepresented in the absence of Fra-2, indicating altered selection of iNKT cells. There is also widespread dysregulation of AP-1-directed gene expression. In the periphery, mature Fra-2-deficient iNKT cells are able to participate in an immune response, but they have an altered response to Ag, showing increased expansion and producing increased amounts of IL-2 and IL-4 compared with their wild-type counterparts. Unusually, naive Fra-2-deficient T cells also rapidly produce IL-2 and IL-4 upon activation. Taken together, these data define Fra-2 as necessary for regulation of normal iNKT cell development and function, and they demonstrate the central role played by the AP-1 family in this lineage.
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 Cancer Research UK and the Institute of Cancer Research (to K.W.), as well as by Cancer Research UK Grant C399/A2291 (to V.C.).
V.L., D.M., V.C., J.S., and K.W. designed experiments; V.L. and J.S. conducted experiments; and V.L. and K.W. prepared the manuscript.
2 Current address: National Institute of Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, U.K.
3 Current address: Cancer Research U.K. London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3PX, U.K.
4 Address correspondence and reprint requests to Dr. Kathleen Weston, Section of Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom. E-mail address: kathy.weston{at}icr.ac.uk
5 Abbreviations used in this paper: DP, CD4+CD8+ double-positive; BATF, basic leucine zipper transcription factor, ATF-like; iNKT, invariant NKT cell; 
-GalCer, -galactosylceramide; WT, wild type.
6 The online version of this article contains supplemental material.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
