Stepwise progression of β-selection during T cell development involves histone deacetylation

Abstract

During T cell development, the first step in creating a unique T cell receptor (TCR) is genetic recombination of the TCRβ chain. The quality of the new TCRβ is assessed at the β-selection checkpoint. Most cells fail this checkpoint and die, but the coordination of fate at the β-selection checkpoint is not yet understood. We shed new light on fate determination during β-selection using a selective inhibitor of histone deacetylase 6, ACY1215. ACY1215 disrupted the β-selection checkpoint. Characterising the basis for this disruption revealed a new, pivotal stage in β-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 β-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 β-selection checkpoint.

Human T cell development and aging: Remodeling throughout the lifespan

“…This involves the V(D)J recombination process, which includes many genes and enzymes, such as RAG1, RAG2, TdT, and Artemis [32]. At the DN3 stage, TCRβ chain gene rearrangement is completed and expressed on the cell surface, paired with pre-assembled TCRα chains to form the pre-TCR [33]. Successful assembly of the pre-TCR triggers intracellular signaling that promotes T cell precursors to pass through β-selection, transitioning from the DN3 stage to the DN4 stage [34,35] .…”

E-cadherin in developing murine T cells controls spindle alignment and progression through β-selection

“…The engagement of the pre-TCR with peptide-bound MHC both enables a broadening of the ultimate β chain repertoire and prevents dedifferentiation (15)(16)(17). However, given the lack of co-receptors at the βselection stage (18) and the weak binding of the pre-TCR compared with the TCRαβ of mature T cells, it seems likely that these cells would need more help to maintain an interaction sufficiently strong to support TCR signaling and polarization, particularly in the context of competition for the niche.…”