Aberrant selection and function of invariant NKT cells in the absence of AP-1 transcription factor Fra-2.
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 TCRVbeta8 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.
Lawson
Victoria J
VJ
Section of Cell and Molecular Biology, Institute of Cancer Research, London, United Kingdom.
Maurice
Diane
D
Silk
Jonathan D
JD
Cerundolo
Vincenzo
V
Weston
Kathleen
K
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D051921:Fos-Related Antigen-2 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D017353:Gene Deletion; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000502:physiology
D051921:Fos-Related Antigen-2; C497873:Fosl2 protein, mouse; D007376:Interleukin-2; D018808:Transcription Factor AP-1; D015847:Interleukin-4