Modulation of hematopoiesis in mice with a truncated mutant of the interleukin-2 receptor γ chain

The interleukin-2 (IL-2) receptor γ chain is indispensable for IL-2-, IL- 4-, IL-7-, IL-9-, and IL-15-mediated signaling. Mutations of the human γ chain cause the X-linked severe combined immunodeficiency (XSCID), showing that T and natural killer cells absolutely require the γ chain for their development in humans. To elucidate the roles of the y chain in hematopoiesis, we have generated mice, by gene targeting, that express a form of the γ chain lacking the cytoplasmic region. Male mice carrying the truncated γ-chain mutant, which mimics mutations in patients with XSCID, showed a decrease in the number of lymphocytes and an increase in monocytes; the number of T cells was profoundly reduced and no natural killer cells were detected, which is similar to the characteristic of human XSCID. Unlike human XSCID, the levels of B cells were also reduced. In spite of the severe decrease in CD45R⁺/sIgM⁺ B cells, the level of IgM in serum of the 8-week- old mutant mice was higher than that of control littermates. Interestingly, the stem cell population with surface phenotypes of CD34, c-kit, and Sca-1 was significantly increased. Furthermore, the colony-forming assay showed that the mutant mice had 15-fold higher numbers of hematopoietic progenitor cells in the spleen as compared with that of controls. These results indicate that functional loss of the γ chain causes significant effects on the immunological system in mice.