RESUMO
A critical stage of T cell development is ß-selection; at this stage, the T cell receptor ß (TCRß) chain is generated, and the developing T cell starts to acquire antigenic specificity. Progression through ß-selection is assisted by low-affinity interactions between the nascent TCRß chain and peptide presented on stromal major histocompatibility complex and cues provided by the niche. In this study, we identify a cue within the developing T cell niche that is critical for T cell development. E-cadherin mediates cell-cell interactions and influences cell fate in many developmental systems. In developing T cells, E-cadherin contributed to the formation of an immunological synapse and the alignment of the mitotic spindle with the polarity axis during division, which facilitated subsequent T cell development. Collectively, these data suggest that E-cadherin facilitates interactions with the thymic niche to coordinate the ß-selection stage of T cell development.
Assuntos
Caderinas , Linfócitos T , Animais , Camundongos , Caderinas/metabolismo , Comunicação Celular , Receptores de Antígenos de Linfócitos T alfa-beta , Linfócitos T/citologia , Linfócitos T/metabolismo , Timo , Fuso Acromático/metabolismoRESUMO
During T cell development, the first step in creating a unique T cell receptor (TCR) is genetic recombination of the TCRß chain. The quality of the new TCRß is assessed at the ß-selection checkpoint. Most cells fail this checkpoint and die, but the coordination of fate at the ß-selection checkpoint is not yet understood. We shed new light on fate determination during ß-selection using a selective inhibitor of histone deacetylase 6, ACY1215. ACY1215 disrupted the ß-selection checkpoint. Characterising the basis for this disruption revealed a new, pivotal stage in ß-selection, bookended by up-regulation of TCR co-receptors, CD28 and CD2, respectively. Within this "DN3bPre" stage, CD5 and Lef1 are up-regulated to reflect pre-TCR signalling, and their expression correlates with proliferation. These findings suggest a refined model of ß-selection in which a coordinated increase in expression of pre-TCR, CD28, CD5 and Lef1 allows for modulating TCR signalling strength and culminates in the expression of CD2 to enable exit from the ß-selection checkpoint.