Homotypic Interactions Mediated by Slamf1 and Slamf6 Receptors Control NKT Cell Lineage Development

Griewank, Klaus G.; Borowski, Christine; Rietdijk, Svend; Wang, Ninghai; Julien, Aimée; Wei, Datsen G.; Mamchak, Alusha A.; Terhorst, Cox; Bendelac, Albert

doi:10.1016/j.immuni.2007.08.020

Cited by 307 publications

(387 citation statements)

References 70 publications

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“…Homotypic interactions between immature developing T cells are required to specify lineage commitment and differentiation; for example, T-cell-T-cell adhesion promotes SLAM family member interactions required to drive natural killer T-cell dif- ferentiation (25). Similarly, thymocyte-thymocyte interactions promote CD4 cell selection in the presence of MHC IIexpressing thymocytes (26).…”

Section: Discussionmentioning

confidence: 99%

Immature T-cell clustering and efficient differentiation require the polarity protein Scribble

Pike

Kulkarni

Pawson

2010

Proc. Natl. Acad. Sci. U.S.A.

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T-cell polarization is required for cell migration and cell-cell interactions, cellular behaviors crucial for lymphocyte differentiation. Despite expression of the epithelial polarity network in T cells, neither its contribution to thymocyte polarity nor its requirement during development is known. We report here that depletion of the polarity protein Scribble in hematopoietic progenitor cells results in inefficient T-cell development characterized by a partial developmental block during the early double-negative (DN) stage of differentiation. Scribble-depleted hematopoietic progenitor cells exhibit a delayed transition into late CD44 lo/− CD25 + DN3 cells, evidenced by the accumulation of early CD44 int CD25 + DN3 cells. As a consequence, a limited cellular expansion and a reduced frequency of intracellular T-cell receptor β-positive DN3 cells are observed among Scribble-deficient differentiating T cells. Moreover, whereas purified Scribble-depleted DN2 and DN3 cells do not exhibit compromised spontaneous motility, T-cell clustering and prolonged homotypic interactions among such cells are reduced. This deficiency correlates with a lack of polarization of the integrin LFA-1 during T-cell migration or on the initiation of T-cell-T-cell interactions. Scribble is therefore a critical contributor to the clustering of immature T cells, an event shown here to be necessary for efficient developmental progression.

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Section: Discussionmentioning

confidence: 99%

Immature T-cell clustering and efficient differentiation require the polarity protein Scribble

Pike

Kulkarni

Pawson

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…To determine the mechanisms by which Dicer deletion impaired iNKT cell development, we first investigated whether DP thymocytes from cd4Dicer ⌬/⌬ mice exhibited defective CD1d expression, CD1d-dependent lipid Ag presentation or expression of the SLAMF molecules shown to play a role in iNKT cell development (23). DP thymocytes from cd4Dicer ⌬/⌬ and Dicer lox/lox littermate control mice expressed similar levels of CD1d and presented with comparable efficiency the exogenous glycolipid ␣GalCer to an iNKT cell hybridoma (supplemental Fig.…”

Section: The Inkt Cell Developmental Defect Caused By Dicer Deficiencmentioning

confidence: 99%

Dicer-Dependent MicroRNA Pathway Controls Invariant NKT Cell Development

Fedeli

Napolitano

Wong

et al. 2009

The Journal of Immunology

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Invariant NK T (iNKT) cells are a separate lineage of T lymphocytes with innate effector functions. They express an invariant TCR specific for lipids presented by CD1d and their development and effector differentiation rely on a unique gene expression program. We asked whether this program includes microRNAs, small noncoding RNAs that regulate gene expression posttranscriptionally and play a key role in the control of cellular differentiation programs. To this aim, we investigated iNKT cell development in mice in which Dicer, the RNase III enzyme that generates functional microRNAs, is deleted in cortical thymocytes. We find that Dicer deletion results in a substantial reduction of iNKT cells in thymus and their disappearance from the periphery, unlike mainstream T cells. Without Dicer, iNKT cells do not complete their innate effector differentiation and display a defective homeostasis due to increased cell death. Differentiation and homeostasis of iNKT cells require Dicer in a cell-autonomous fashion. Furthermore, we identify a miRNA profile specific for iNKT cells, which exhibits features of activated/effector T lymphocytes, consistent with the idea that iNKT cells undergo agonist thymic selection. Together, these results define a critical role of the Dicer-dependent miRNA pathway in the physiology of iNKT cells.

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“…4A) and Fnip1 −/− mice ( Fig. 2A), suggesting that other intrinsic cellular programs of iNKT cells are required to proceed beyond stage 1 (31)(32)(33).…”

Section: Expression Of Vα14jα18 Transgene Does Not Rescue Inkt Cellmentioning

confidence: 97%

Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development

Park

Tsang

Iritani

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Folliculin-interacting protein 1 (Fnip1) is an adaptor protein that physically interacts with AMPK, an energy-sensing kinase that stimulates mitochondrial biogenesis and autophagy in response to low ATP, while turning off energy consumption mediated by mammalian target of rapamycin. Previous studies with Fnip1-null mice revealed that Fnip1 is essential for pre-B-cell development. Here we report a critical role of Fnip1 in invariant natural killer T (iNKT) cell development. Thymic iNKT development in Fnip1 −/− mice was arrested at stage 2 (NK1.1 − CD44 + ) but development of CD4, CD8, γδ T-cell, and NK cell lineages proceeded normally. Enforced expression of a Vα14Jα18 iNKT TCR transgene or loss of the proapoptotic protein Bim did not rescue iNKT cell maturation in Fnip1 −/− mice. Whereas most known essential transcription factors for iNKT cell development were represented normally, Fnip1 −/− iNKT cells failed to down-regulate Promyelocytic leukemia zinc finger compared with their WT counterparts. Moreover, Fnip1 −/− iNKT cells contained hyperactive mTOR and reduced mitochondrial number despite lower ATP levels, resulting in increased sensitivity to apoptosis. These results indicate that Fnip1 is vital for iNKT cell development by maintaining metabolic homeostasis in response to metabolic stress. metabolism | thymus | Birt-Hogg-Dubé syndrome

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Homotypic Interactions Mediated by Slamf1 and Slamf6 Receptors Control NKT Cell Lineage Development

Cited by 307 publications

References 70 publications

Immature T-cell clustering and efficient differentiation require the polarity protein Scribble

Immature T-cell clustering and efficient differentiation require the polarity protein Scribble

Dicer-Dependent MicroRNA Pathway Controls Invariant NKT Cell Development

Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development

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