Cytokines in the induction and circumvention of peripheral tolerance

Injection of deaggregated (monomeric) human gamma globulin (DHGG) into mice induces a state of immunological tolerance to subsequent challenge with immunogenic forms of HGG. Tolerance was shown to be induced in both the Th1 and Th2 CD4+ subsets. These mice fail to demonstrate antibody production, T cell proliferation, cytokine release, or T cell helper function. On the other hand, simultaneous injection of lipopolysaccharide (LPS) as well as interleukin-1 (IL-1) was capable of interfering with the induction of tolerance to DHGG. The purpose of the present study is to extend these investigations to determination of the cellular mechanisms responsible for the interference of tolerance induction in both CD4+ T cell subsets. It was demonstrated that LPS and IL-1 have differential effects on the induction of tolerance in the CD4+ subsets. As evidenced by immunoglobulin G (IgG) subclass, T helper cell function, and lymphokine secretion, coinjection of LPS with tolerogen interfered with the induction of tolerance in both subsets, whereas IL-1 interfered with the induction of tolerance exclusively in the Th1 subset. LPS and IL-1 had differential effects on the interference of the induction of tolerance in LPS-resistant mice where IL-1, but not LPS, was effective. In contrast to IL-1, IL-12 injected along with DHGG failed to interfere with the induction of tolerance in either Th1 or Th2 cells. Previous studies that demonstrated tolerance in the DHGG models induced in both the Th1 and Th2 subsets was further suggested by the demonstrations in the present study that dose-response curves for the induction of tolerance are identical in both subsets. The above findings taken together are compatible with the suggestion that tolerance induction results from the lack of cytokine production, which then prevents the expansion of Th1 and Th2 subsets following activation of the CD4+ precursor T cell. Furthermore, they support the general opinion that the expansion of these two subsets involve different cytokine pathways and that LPS and IL-1 most likely act through different cell receptors.