Transcription Factor Fra-2 NKT Cells in the Absence of AP-1 Aberrant Selection and Function of Invariant

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 TCRV␤8 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. D uring T cell development, a diverse array of thymocytes with differing Ag specificities is generated through rearrangement of TCR genes and random pairing of TCR␣-and TCR␤-chains. These cells undergo selection on the basis of their affinity for peptide-MHC, and those surviving selection commit to, and acquire the effector functions associated with, CD4 ϩ " helper " , CD8 ϩ " cytotoxic " , or CD4 ϩ CD25 ϩ regulatory lineages. In parallel, thymocytes bearing the V␣14-J␣18 TCR␣-chain rearrangement are selected into the iNKT lineage (1–3). In contrast to conventional T cells, which are selected on peptide-MHC complexes displayed by thymic epithelial cells, iNKT cells are selected from the CD4 ϩ CD8 ϩ double-positive (DP) 5 thymocyte population by other DP thymocytes (4, 5), and respond to glycolipid Ags presented by the nonpolymorphic, MHC class I-like molecule CD1d (6). While the identity of the selecting ligand for iNKT cells remains contentious, mature iNKT cells respond to a variety of Ags, including the glyco-sphingolipid ␣-galactosylceramide (␣-GalCer) (7). In response to cognate Ag, mature iNKT cells very rapidly produce a range of cytokines, and this, along with their ability to indirectly modulate the activity of other immune cells, endows them with potent immunoregulatory properties (1). The signaling requirements for the divergence of iNKT cells from other T lineages are not fully understood. In common with T …