Early events in the thymus affect the balance of effector and regulatory T cells

In cellular immunology the critical balance between effector and regulatory mechanisms is highlighted by serious immunopathologies attributable to mutations in Foxp3 , a transcription factor required for a major subset of regulatory T (T r ) cells 1 , 2 , 3 . Thus, many studies have focused on the developmental origin of T r cells, with the prevailing view that they emerge in the thymus from late-stage T-cell progenitors whose T-cell receptors (TCRs) engage high affinity (agonist) ligands 4 , 5 , 6 . This study questions the completeness of that interpretation. Here we show that without any obvious effect on TCR-mediated selection, the normal differentiation of mouse γδ T cells into potent cytolytic and interferon-γ-secreting effector cells is switched towards an aggregate regulatory phenotype by limiting the capacity of CD4 + CD8 + T-cell progenitors to influence in trans early γδ cell progenitors. Unexpectedly, we found that the propensity of early TCR-αβ + progenitors to differentiate into Foxp3 + T r cells is also regulated in trans by CD4 + CD8 + T-cell progenitor cells, before agonist selection.