Abstract
Suppression of T-cell growth is an important mechanism for establishment of self-tolerance and prevention of unwanted prolonged immune responses that may cause tissue damage. Although negative selection of potentially self-reactive T cells in the thymus as well as in peripheral tissues has been extensively investigated and well documented, regulatory mechanisms to dampen proliferation of antigen-specific effector T cells in response to antigen stimulation remain largely unknown. Thus, in this work, we focus on the identification of growth suppression mechanisms of antigen-specific effector T cells. In order to address this issue, we investigated the cellular and molecular events in growth suppression of an ovalbumin (OVA)-specific T-cell clone after stimulation with a wide range of OVA-peptide concentrations. We observed that while an optimal dose of peptide leads to cell cycle progression and proliferation, higher doses of peptide reduced cell growth, a phenomenon that was previously termed high-dose suppression. Our analysis of this phenomenon indicated that high-dose suppression is a consequence of cell cycle arrest, but not Fas-Fas ligand-dependent apoptosis or T-cell anergy, and that this growth arrest occurs in S phase, accompanied by reduced expression of CDK2 and cyclin A. Importantly, inhibition of MEK/ERK activation eliminated this growth suppression and cell cycle arrest, while it reduced the proliferative response to optimal antigenic stimulation. These results suggest that cell cycle arrest is the major mechanism regulating antigen-specific effector T-cell expansion, and that the MEK/ERK signaling pathway has both positive and negative effects, depending on the strength of antigenic stimulation.