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(1-3). 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(4-6). 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 gamma delta T cells into potent cytolytic and interferon-gamma-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 gamma delta cell progenitors. Unexpectedly, we found that the propensity of early TCR-alpha beta(+) progenitors to differentiate into Foxp3 1 T(R) cells is also regulated in trans by CD4(+) CD8(+) T-cell progenitor cells, before agonist selection.