Suppression of T lymphocyte functions by human C3 fragments. I. Inhibition of human T cell proliferative responses by a kallikrein cleavage fragment of human iC3b.

Cleavage of human iC3b by kallikrein isolated from human plasma generates a fragment, C3d-K, which is capable of inhibiting mitogen-, antigen-, and alloantigen-induced T lymphocyte proliferation. Native C3, C3a, C3b, and C3c-K had no effect on lymphocyte proliferative responses. In addition to being a potent suppressor of mitogen- and antigen-induced proliferation, C3d-K is capable of inducing leukocytosis in both mice and rabbits. Intravenous injection of C3d-K, but not C3, C3a, C3b, or C3c-K, results in a twofold to threefold increase in the number of circulating leukocytes. Thus, C3d-K exhibits two apparently independent functions, namely suppression of T cell proliferation and leukocytosis. Cleavage of iC3b by kallikrein results in the production of only two fragments. The larger fragment, C3c-K, is 144,000 m.w. and has a chemical structure analogous to that of C3c obtained from the cleavage of C3 by trypsin or elastase. The smaller fragment, C3d-K, is 41,000 m.w. and contains the metastable binding site of C3. It is through this site located in the C3d region of the molecule that C3 attaches covalently to target cells. Analysis of the amino terminal region of C3d-K provided a sequence that fails to overlap with any sequence yet reported for other characterized C3 fragments, including C3d originally obtained from elastase digestion. A revised model of the C3 molecule is proposed, with locations of the C3e and C3d fragments assigned on the basis of chemical analyses.