T-bet concomitantly controls migration, survival, and effector functions during the development of Vα14i NKT cells

Abstract

V␣14i natural killer T (NKT)-cell function has been implicated in a number of disease conditions. The molecular events that drive V␣14i NKT-cell development remain elusive. We recently showed that T-bet is required for the terminal maturation of these cells. Here we identify some of the genetic targets of T-bet during V␣14i NKT-cell lineage development. Microarray gene-expression analyses on developing V␣14i NKT cells were performed and provide a molecular framework to study these maturation events. In vitro ectopic expression of T-bet in immature V␣14i NKT cells, which do not yet express T-bet, was sufficient to promote V␣14i NKT-cell maturation, driving the expression of multiple genes, including those that participate in migration, survival, and effector func- IntroductionNatural killer T (NKT) cells are a unique lymphocyte lineage that coexpresses a rearranged T-cell receptor (TCR) in association with the CD3 complex as well as several receptors first identified on bona fide NK cells, such as NK1.1, the interleukin-2 (IL-2)/15R␤ chain (CD122) and various Ly49 molecules. 1 Most NKT cells in the mouse express a semi-invariant TCR composed of a V␣14-J␣18 rearrangement that preferentially associates with either V␤8, V␤7, or V␤2, 2 and are positively selected by CD1d, a nonclassical major histocompatibility (MHC) class I molecule. We refer to this CD1d reactive subgroup as V␣14 invariant (V␣14i) NKT cells to distinguish them from other populations of NKT cells that have been defined. 3,4 The early and potent cytokine secretion by V␣14i NKT cells following TCR stimulation may provide an important link between the innate and adaptive immune systems. 3,5 Consistent with this, V␣14i NKT cells appear to be important for responses to tumors, infectious agents, the maintenance of self tolerance, and the prevention of autoimmunity. 1,3 Recent progress has been made in identifying V␣14i NKT-cell developmental intermediates. [6][7][8][9] V␣14i NKT cells develop from CD4 ϩ CD8 ϩ double-positive (DP) V␣14-J␣18 TCR ϩ thymocyte precursors. 6,[10][11][12] Following positive selection by CD1d molecules, V␣14i NKT cells undergo a maturation process defined by the sequential up-regulation of diverse markers and the late fate specification of the NKT-cell lineage. 6-9 NKT-cell precursors can be identified on the basis of TCR specificity in the thymus of young mice using the CD1d tetramer. These cells are phenotypically indistinguishable from conventional mature lymphocytes, being HSA low , CD44 low , and NK1.1 Ϫ . 7 This phenotype is defined as stage 1. 13 Ontogeny and transfer studies defined a developmental sequence from CD44 low NK1.1 -(stage 1) to CD44 high NK1.1 -(stage 2). At this latter stage, V␣14i NKT cells are still considered immature but can leave the thymus and colonize peripheral organs. 7,8 A final maturation step that occurs either in the thymus or in the peripheral organs is accompanied by the expression of NK1.1, Ly49 receptors and CD122 (stage 3). 7,8,14 Interestingly, these 3 developmental intermediates each ha...

CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system

“…Interestingly, mRNAs encoding for members of the RNA-recognition-motif family of RNA-binding proteins, TIA-1 and TIAR, have been found enriched in iNKT cells [32,33]. mRNAs encoding for the chemokine RANTES (CCL5) have also been found to be constitutively expressed in iNKT cells [32,33], and a similar mechanism of post-transcriptional regulation of RANTES expression in memory "conventional" T cells has been described [34,35]. Altogether, these results suggest the possibility that iNKT might regulate, at least to some extent, their cytokine secretion through such a translational mechanism.…”

Temporal Dissection of T-bet Functions

“…In addition to Th1 cells, T-bet is detected in several other immune cells, including CD8 ϩ T cells (3,5,6), dendritic cells (7), B cells (8), NK cells and NKT cells (9 -11). T-bet regulates expression of numerous immune systemassociated genes, including cytokines (4), cytokine receptors (9 -12), chemokines (7,11), chemokine receptors (4,11,13) and cytotoxicity (9,11). Altogether these results have established T-bet as an essential transcription factor in the generation and regulation of proper immune responses.…”

“…3A). We reported previously that ectopic expression of T-bet in T-bet Ϫ/Ϫ NKT cells induces expression of IL-2/IL-15R␤ (CD122) mRNA and cell surface expression of CD122 (10,11). Furthermore, recent data have emphasized the critical role of T-bet and its homolog Eomes in enhancing CD122 expression and consequently in controlling the survival of IL-15-dependent cells, including NKT, NK, and CD8 memory cells (9).…”

“…Furthermore, recent data have emphasized the critical role of T-bet and its homolog Eomes in enhancing CD122 expression and consequently in controlling the survival of IL-15-dependent cells, including NKT, NK, and CD8 memory cells (9). In addition, T-bet has been involved in the control of Th1 cell migration to inflammatory sites through its regulation of expression of the chemokine receptor CxCR3 (11,13). Altogether these results emphasize the importance of T-bet in regulating CD122 and CxCR3 expression in addition to IFN-␥.…”

Editorial overview

“…Finally, the many functions that have been attributed to iNKT cells, as likened to the many functions of a Swiss army knife, are summarized in a sixth review by Laurent Gapin et al This comprehensive article includes a succinct overview of the characteristics of iNKT cells, and outlines new findings concerning their development [e.g. [7]}. Plausible mechanisms for how a given cell type could have so many different functions are also put forth.…”