The differentiation of thymocytes into the ab or gd lineage occurs at the β-selection checkpoint. Differences in the signal strength of the gd T cell antigen receptor (TCR) or precursor TCR are thought to govern this lineage fate, albeit in a ligand-independent way. In Science Signaling, Pennington and colleagues rule out previous models that suggested that surface receptor oligomerization controls this selection process. Thymocytes deficient in the precursor to TCRα (preTα) reconstituted with a natural splice variant encoding preTα that lacks a charged immunoglobulin-like domain that mediates receptor oligomerization are able to drive cells to proliferate and differentiate to the double-positive stage. Similarly, transfection of RAG2-deficient thymocytes with gd TCR constructs that lack extracellular domains, which thereby prevents receptor oligomerization, can still promote double-positive differentiation of gd thymocytes. The formation of signaling-competent gd TCR or TCRβ–pre-Tα in double-negative thymocytes seems to be the minimum requirement for cell progression. Thus, the authors argue that signal-strength differences are probably due to regulation of receptor abundance.

Sci. Signal. (19 July 2011) doi:10.1126/scisignal.2001765