2009
DOI: 10.4049/jimmunol.0803577
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Aberrant Selection and Function of Invariant NKT Cells in the Absence of AP-1 Transcription Factor Fra-2

Abstract: 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 a… Show more

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Cited by 25 publications
(20 citation statements)
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“…A previous report that JunB is part of a gene network preferentially upregulated in i NKT cells compared to NK cells and conventional T cells is consistent with our findings 13 . While indirect evidence through overexpression or deficiency of the negative regulator BATF shows that AP-1 activity promotes generation of i NKT cells 44,45 , lack of the Fos family member Fra2 leads to increased i NKT cell numbers 46 . Interestingly, JunB/AP1 directly controls expression of Ifng , a hallmark cytokine released by mature i NKT cells 47 .…”
Section: Discussionmentioning
confidence: 99%
“…A previous report that JunB is part of a gene network preferentially upregulated in i NKT cells compared to NK cells and conventional T cells is consistent with our findings 13 . While indirect evidence through overexpression or deficiency of the negative regulator BATF shows that AP-1 activity promotes generation of i NKT cells 44,45 , lack of the Fos family member Fra2 leads to increased i NKT cell numbers 46 . Interestingly, JunB/AP1 directly controls expression of Ifng , a hallmark cytokine released by mature i NKT cells 47 .…”
Section: Discussionmentioning
confidence: 99%
“…However, some of these experiments involved the use of mutant mice on mixed genetic backgrounds, which may influence the size of the NKT cell population and subsets defined by NK1.1 expression 29 , 30 . An additional concern is that nfκb1 −/− mutation also destabilizes the tumor progression locus 2 (Tpl2) protein, 31 a key component of the MAPK/extracellular signal‐regulated kinase (ERK) signaling pathway, which has also been implicated in NKT cell development 32 . Therefore, we wanted to revisit the question of how NFκB family members influence NKT cell development and have carried out a comprehensive analysis of these cells in mice lacking individual classical NF‐κB transcription factors (p50‐NF‐κB1, c‐Rel and RelA, as well as p50‐NF‐κB1 × c‐Rel double mutants and Tpl2 mutants), using mice that are fully backcrossed to the C57BL/6 strain background.…”
mentioning
confidence: 99%
“…Deletion of BATF did not lead to changes in Va14i NKT thymocyte numbers, although peripheral Va14i NKT cells were increased in BATF-deficient animals (Betz et al 2010;Jordan-Williams et al 2013). However, a T-cell specific deletion of the Fos family member Fra-2/Fosl2 led to significantly increased numbers of Va14i NKT thymocytes (Lawson et al 2009). It is has not been determined what stages of Va14i NKT cell development were impacted by these perturbations of AP-1 activity, however, the known roles of these factors in regulating cell proliferation and survival suggest the possibility that AP-1 factors are important for the expansion of the Va14i NKT thymocyte pool.…”
Section: Ap-1 Transcription Factorsmentioning
confidence: 94%
“…Peripheral Va14i NKT cell activation is also regulated by AP-1 factors, as demonstrated by the effects of a T-lineage specific deletion of Fra2/Fosl2 (Lawson et al 2009). Splenic Va14i NKT cells from CD4-cre Fosl2 f/f mice that were stimulated with aGalCer in vivo exhibit enhanced proliferative expansion.…”
Section: Localization and Functionmentioning
confidence: 99%