Cell cycle arrest caused by MEK/ERK signaling is a mechanism for suppressing growth of antigen-hyperstimulated effector T cells

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 resu...
Source: International Immunology - Category: Allergy & Immunology Authors: Tags: Original Research Source Type: research