Murine bone marrow was infected with a helper-free recombinant retrovirus expressing the mIL-7 gene and used to reconstitute lethally irradiated hosts. Twenty-three percent of mIL-7 retrovirus-infected recipients became moribund within 4-16 wk posttransplant with splenomegaly and hyperplastic lymph nodes, elevated white blood cell counts, plus other noticeable abnormalities including, in one animal, lymphocytic ascites. FACS analysis of hematopoietic tissue in diseased mice revealed marked alterations in T cell subsets of spleen and lymph nodes. These differences in extrathymic tissues compared with control animals included increases in CD4(-)-CD8+ lymphocytes and most strikingly the appearance of large numbers of an unusual CD4(+)-CD8+ T cell population with other characteristics of immature thymocytes (CD3lo-Thy1(+)-HSAhi). 3H-thymidine incorporation assays performed on extrathymic lymphocytes from a lymph node or ascites of two affected mice showed high levels of proliferation in the absence of either CD3 cross linking or exogenous IL-7 stimulation. Interestingly, in contrast to the effects noted on peripheral lymphoid tissues, no alteration in thymic size was noted and the proportion of CD4(+)-CD8+ cells was generally decreased with corresponding increases in CD4+ or CD8+ or CD4(-)-CD8- cells. These results provide further evidence of the involvement of IL-7 in the development and proliferation of early T cells in vivo and point to the possibility of IL-7 involvement in extrathymic expansion of a primitive class of T cells, the functional nature of which remains to be elucidated.