Different levels of T-Cell receptor triggering induce distinct functions in hepatitis B and hepatitis C virus-specific human CD4(+) T-Cell clones

CD4+ T cells play a major role in the host defense against viruses and intr acellular microbes. During the natural course of such an infection, specifi c CD4+ T cells are exposed to a wide range of antigen concentrations depend ing on the body compartment and the stage of disease. While epitope variant s trigger only subsets of T-cell effector functions, the response of virus- specific CD4(+) T cells to various concentrations of the wild-type antigen has not been systematically studied. We stimulated hepatitis B virus core- and hepatitis C virus NS3-specific CD4(+) T-cell clones which had been isol ated from patients with acute hepatitis during viral clearance with a wide range of specific antigen concentrations and determined the phenotypic chan ges and the induction of T-cell effector functions in relation to T-cell re ceptor internalization. A low antigen concentration induced the expression of T-cell activation markers and adhesion molecules in CD4(+) T-cell clones in the absence of cytokine secretion and proliferation. The expression of CD25, HLA-DR, CD69, and intercellular cell adhesion molecule 1 increased as soon as T-cell receptor internalization became detectable. A 30- to 100-fo ldhigher antigen concentration, corresponding to the internalization of 20 to 30% of T-cell receptor molecules, however, was required for the inductio n of proliferation as well as for gamma interferon and interleukin-4 secret ion. These data indicate that virus-specific CD4(+) T cells can respond to specific antigen in a graded manner depending on the antigen concentration, which may have implications for a coordinate regulation of specific CD4(+) T-cell responses.