Key Points

CD8+ TEMRA cells respond better to IL-15 than do CD8+ TEM cells.

CD5 negatively regulates IL-15–induced proliferation of memory CD8+ T cells.

CD5 suppresses IL-15–induced proliferation by inhibiting the mTOR pathway.

Visual AbstractAbstract

IL-15 induces the proliferation of memory CD8+ T cells as well as NK cells. The expression of CD5 inversely correlates with the IL-15 responsiveness of human memory CD8+ T cells. However, whether CD5 directly regulates IL-15–induced proliferation of human memory CD8+ T cells is unknown. In the current study, we demonstrate that human memory CD8+ T cells in advanced stages of differentiation respond to IL-15 better than human memory CD8+ T cells in stages of less differentiation. We also found that the expression level of CD5 is the best correlate for IL-15 hyporesponsiveness among human memory CD8+ T cells. Importantly, we found that IL-15–induced proliferation of human memory CD8+ T cells is significantly enhanced by blocking CD5 with Abs or knocking down CD5 expression using small interfering RNA, indicating that CD5 directly suppresses the IL-15–induced proliferation of human memory CD8+ T cells. We also found that CD5 inhibits activation of the mTOR pathway, which is required for IL-15–induced proliferation of human memory CD8+ T cells. Taken together, the results indicate that CD5 is not just a correlative marker for IL-15 hyporesponsiveness, but it also directly suppresses IL-15–induced proliferation of human memory CD8+ T cells by inhibiting mTOR pathways.

Footnotes

This work was supported by Samsung Science and Technology Foundation Project SSTF-BA1402-51 and by Institute for Basic Science, Republic of Korea Project IBS-R801-D2.

Y.J.C., H.L., and E.-C.S. designed the study. Y.J.C., H.L., J.H.K., M.S., and S.-Y.K. performed the experiments. Y.J.C., H.L., J.H.K., J.-Y.K, S.-H.P., and E.-C.S. analyzed the data. Y.J.C., H.L., and E.-C.S. wrote and edited the manuscript.

The online version of this article contains supplemental material.

Abbreviations used in this article:

γccommon γ-chainHCMVhuman CMVIAVinfluenza A virusMHC-IMHC class INSGNOD.SCID.γc-deficientsiRNAsmall interfering RNATEMeffector memory TTEMRACD45RA+ effector memory TReceived August 31, 2021.Accepted July 20, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.