The discovery of new cytokines normally relies on a prior knowledge of at least one of their biological effects, which is used as a criterion either for the purification of the protein or for the isolation of the complementary DNA by expression cloning. However, the redundancy of cytokine activities complicates the discovery of novel cytokines in this way, and the pleiotropic nature of many cytokines means that the principal activities of a new cytokine may bear little relation to that used for its isolation. We have adopted an alternative approach which relies on differential screening of an organized subtracted cDNA library from activated peripheral blood mononuclear cells, using the inducibility of lymphokine messenger RNAs by anti-CD28 as a primary screening criterion. The ligation of the CD28 antigen on the T lymphocyte by a surface antigen, B7/BB-1, expressed on activated B lymphocytes and monocytes is a key step in the activation of T lymphocytes and the accumulation of lymphokine mRNAs. Here we report the discovery by molecular cloning of a new interleukin (interleukin-13 or IL-13) expressed in activated human T lymphocytes. Recombinant IL-13 protein inhibits inflammatory cytokine production induced by lipopolysaccharide in human peripheral blood monocytes. Moreover, it synergizes with IL-2 in regulating interferon-gamma synthesis in large granular lymphocytes. Recent mapping of the IL-13 gene shows that it is closely linked to the IL-4 gene on chromosome 5q 23-31 (ref. 4). Interleukin-13 may be critical in regulating inflammatory and immune responses.