[Is it possible to treat diseases by manipulation of lymphocytes?]

Two signals are required for activation of T lymphocytes. Formation of tri-molecular complex among T cell antigen receptor(TCR), major histocompatibility complex(MHC) molecule, and antigen peptide produces signal 1 via TCR. Thus, signal 1 is antigen-dependent. However, signal 2 is elicited by interaction between CD28 and its ligands(CD80 and CD86) and is antigen-independent. Interestingly, cell surface expression of CD80 and CD86 on antigen-presenting cell(APC) is regulated by stimulus via CD40. In this review, it is shown that enhancement of signal 2 by agonistic anti-CD40 antibody increases immune responses, resulting in reinforcement of vaccine efficacy against influenza viruses and murine tumors, if antigen-dependent signal 1 is properly provided. In contrast, inhibition of signal 2 by anti-CD40 ligand(CD154) with pathogenic peptide K2 for EAU(experimental autoimmune uveoretinitis) tolerates T lymphocytes specific for K2, resulting in amelioration of EAU. Accordingly, herein, the possibility of application to humans for immunomanipulation with a controlled stimulus via CD40 is discussed.