title: Immature T-cell clustering and efficient differentiation require the polarity protein Scribble.
abstract: 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.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Pike
authors.forename: Sarang
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
mesh_terms: D000818:Animals; D002449:Cell Aggregation / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D016764:Cell Polarity / Q000276:immunology*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C508433:scrib protein, mouse