T-cell receptor (TCR) genes need to be rearranged by a site specific-VDJ recombinase before they are expressed. This process, initiated in CD44+25+ thymocytes, takes place during the early stage of T-cell differentiation in the thymus. Interleukin-7 receptor alpha chain knockout (IL-7R-/-) mice are severely deficient in B-lymphocytes and alpha beta T-cells and completely lack the gamma delta T-cell lineage. Thymocyte development is arrested at a very early stage (DN CD44+CD25-). Because this arrest is earlier than in mice with a block in VDJ recombination, we examined the rearrangement status of TCR genes in thymocytes from IL-7R-/- mice. The TCR beta locus showed a nearly normal pattern of VDJ rearrangements, consistent with the presence of alpha beta T-cells in these mice. However, TCR gamma locus rearrangement was absent or severely reduced for all the V gamma genes analyzed (V gamma 3, V gamma 4, V gamma 1.1, V gamma 1.2 and V gamma 2). In contrast, the delta locus showed little reduction in rearrangement. The defect in gamma rearrangements in IL-7R-/- thymocytes is not simply due to an absence of mature gamma delta T-cells, since TCR delta-/- mice, which also have only alpha beta T-cells, had normal levels of gamma and delta rearrangements. These findings indicate that one or both of the two known ligands of IL-7R, IL-7 and thymic stromal lymphopoietin (TSLP) serves as an extrinsic signal to specifically rearrange the TCR gamma locus.