High concentrations of antigenic ligand activate and do not tolerize naive CD4 T cells in the absence of CD28/B7 costimulation.

We evaluated whether signals transmitted through the T cell receptor (TCR) can activate naive CD4 T cells expressing a transgenic TCR specific for a defined peptide/MHC ligand in the absence of CD28/B7 costimulation. Our results showed that CD28/B7 costimulation was required at low, but not at high, concentrations of antigenic ligand. This was the case whether the CD28/B7 costimulatory pathway was blocked by CTLA-4 Ig fusion protein or by the chemical fixation of antigen-presenting cells. Naive CD4 cells stimulated with high concentrations of antigen and without CD28 costimulation produced low but detectable amounts of IL-2 and interferon-gamma. Furthermore, naive CD4 T cells activated for a 7-day period by either low or high concentrations of antigen with or without CD28 costimulation were functionally similar, indicating that signals transmitted through the TCR were not intrinsically tolerogenic for CD4 T cells.