At low precursor frequencies, the T-cell response to chronic self-antigen results in anergy without deletion

The behavior of self-reactive T cells in the peripheral immune system has often been studied by following the fate of adoptively transferred antigen-specific T cells in antigen expressing mice. In most cases, after a period of expansion, such cells undergo a slow clonal deletion, accompanied by the onset of anergy and/or suppression in the remaining cells. Here, we demonstrate that at initial frequencies approaching those found in normal repertoires, it is possible to completely avoid deletion and still maintain peripheral tolerance. At starting numbers of <1000 T cells, stimulation by chronic self-antigens resulted in a period of robust clonal expansion, followed by a steady plateau phase extending beyond 4 months. Despite their stable persistence, the self-reactive T cells did not convert to a Foxp3+ fate. However, they displayed a considerable block in their ability to make IL-2, consistent with the onset of anergy in a precursor frequency or deletion independent fashion.