LYMPHOID HYPERPLASIA, AUTOIMMUNITY, AND COMPROMISED INTESTINAL INTRAEPITHELIAL LYMPHOCYTE DEVELOPMENT IN COLITIS-FREE GNOTOBIOTIC IL-2-DEFICIENT MICE

IL-2-deficient (IL-2(-/-)) mice develop disorders of the hemopoietic a nd immune systems characterized by anemia, lymphocytic hyperplasia, an d colitis. The mechanisms responsible for these abnormalities remain u nclear, To investigate the underlying basis of autoimmunity, the parti cular role of commensal gut flora in the initiation of colitis, and th e role of IL-2 in the development of intestinal intraepithelial lympho cytes (iIEL), we evaluated IL-2(-/-) mice reared and maintained under gnotobiotic (germfree) conditions, By 8 wk of age, 80% (20 of 25) of g ermfree IL-2(-/-) mice show signs of disease, including anemia, distur bances in bone marrow hemopoietic cells, lymphocytic hyperplasia, and generalized autoimmunity, similar to those seen in specific pathogen-f ree (SPF) IL-2(-/-) mice. In striking contrast to SPF IL-2(-/-) mice, germfree IL-2(-/-) mice do not develop colitis. However, the numbers o f gamma delta(+) and TCR alpha beta(+)CD8 alpha alpha(+) iIELs are red uced, and in lethally irradiated SPF IL-2(+/+) mice, reconstituted wit h IL-2(-/-) bone marrow TCR gamma delta(+) iIELs fail to develop, cons istent with an important role of IL-2/IL-2R signaling in the developme nt of gamma delta iIELs. Consequently, our findings demonstrate that t he colitis seen in SPF IL-2(-/-) mice depends upon the presence of int estinal bacterial flora and that environmental Ags are not responsible for the anemia and extraintestinal lymphoid hyperplasia that occur in IL-2(-/-) mice. Thus, germfree IL-2(-/-) mice represent a unique syst em in which the role of IL-2 deficiency in hemopoietic and immune syst em disorders can be investigated in dissociation from complications th at may arise due to colitis.