Mechanisms underlying enhanced IL-15-induced proliferation of CD45RA Re-Expressing $CD8^+$ T cells

Abstract

Interleukin (IL)-15 is a one of the cytokines sharing common gamma-chain receptor and has a critical role in maintaining basal proliferation of memory $CD8^+$ T cells. However, the response of IL-15 in-duced proliferation varies in different memory subsets of $CD8^+$ T cells and the mechanism is remained to be elucidated. In the present study, we examined IL-15-induced proliferation of memory $CD8^+$ T cells and related mechanisms with human CD45RA re-expressing memory $CD8^+$ T cells ($CD8^+$ Temra cells). First, $CD8^+$ Temra cells were rechecked to have terminally differentiated, senescent characteristics by phenotype analysis and telomere length assessment. Then, I demonstrated that sorted $CD8^+$ Temra cells have enhanced proliferation and cell cycle entry upon IL-15 stimulation in comparison with the oth-er memory $CD8^+$ T cells. Using MHC class I pentamers and in vitro IL-15 stimulation experiments, I found that IL-15-induced proliferation was inversely correlated with CD5 expression, and $CD8^+$ Temra cells express low level of CD5 on their cell surface. Sorted $CD5^{low}$ memory $CD8^+$ T cells exhibited enhanced IL-15-induced proliferation and both blocking and knocking down of CD5 also showed enhanced IL-15-induced proliferation of memory $CD8^+$ T cells indicating that CD5 regulate IL-15-induced proliferation. Then, I revealed that the blockade of CD5 signaling results in increased activation of mechanistic target of rapamycin (mTOR) pathway which is responsible for IL-15-induced proliferation. These results indicate that IL-15-induced proliferation is suppressed by CD5 which inhibits mTOR pathway and that $CD8^+$ Temra cells have increased IL-15-induced proliferation by expressing low level of CD5.