IMMUNE DYSREGULATION IN TGF-BETA-1-DEFICIENT MICE

Approximately 2 wk after birth, mice having a TGF-beta 1 null mutation (TGF-beta 1(-/-)) exhibit a progressive wasting syndrome and death. A ssociated with this phenotype is a multifocal infiltration of lymphocy tes and macrophages into targeted organs, especially the heart, lungs, and salivary glands. To explore the consequences of TGF-beta 1 defici ency on the immune system, lymphocyte phenotype and function were anal yzed. Initially, lymphoid organ architecture seemed to be normal and, as symptoms developed, the thymus decreased in size, whereas lymph nod es were enlarged. Phenotypically, the TGF-beta 1(-/-) lymphoid cells s eemed to be more differentiated in the thymus and activated in the lym ph nodes, but remarkably unaffected in the spleen. Moreover, TGF-beta 1(-/-) spleen and lymph nodes displayed enhanced numbers of proliferat ing cells, as measured by proliferating cell nuclear Ag and/or cyclin- dependent kinase levels. Consistent with this hyperproliferative respo nse, constitutive levels of IL-2 mRNA were elevated in the thymus and both IL-2 and IL-2R mRNA were increased in the lymph nodes. In contras t with the activation profile of TGF-beta 1(-/-) lymphoid cells in viv o, mitogen challenge of these cells in vitro revealed suppressed proli feration that was associated with a defect in inducible IL-2 mRNA expr ession and IL-2 secretion. Moreover, the addition of rIL-2 restored th e deficient mitogen-induced proliferation. The mechanism leading to T cell anergy remains unclear; however, these data confirm the essential role for TGF-beta 1 in maintaining normal immune function.