Role of the common cytokine receptor gamma chain in cytokine signaling and lymphoid development.

To examine the role of gamma c in lymphoid development, we have analyzed mice in which the gamma c gene was specifically inactivated by homologous recombination. These mice also serve as an animal model of human X-linked severe combined immunodeficiency (XSCID). Interestingly, gamma c knockout mice exhibited a somewhat different phenotype than humans with XSCID. Absolute T-cell numbers are greatly diminished in young gamma c-/Y mice, but accumulate with age. gamma delta T cells and NK cells are absent in gamma c-/Y mice and conventional B cells are greatly diminished, yet substantial numbers of peritoneal B-1 cells are present. Since humans with XSCID have essentially no mature T cells, it is especially striking that T cells are readily apparent in gamma c-/Y mice. This observation indicates that in these mice, the gamma c-dependent block in T cell development is less severe than it is in humans. It is possible but unproven that thymic stromal derived lymphopoietin, TSLP, contributes to thymocyte development in these mice. Since B-cell numbers are normal in humans with XSCID, it is also striking that gamma c-/Y mice paradoxically exhibit greatly diminished numbers of B cells. This likely indicates that IL-7 signaling plays a critical role in pre-B cell maturation in mice but is less important in humans. Thus, the abnormalities observed in gamma c-/Y mice have provided clues to assist in dissecting the role of cytokines and their receptors in lymphoid development and have also identified interesting differences in the regulation of this process in mice and humans.