IL-15 inhibits IL-7Rα expression by memory-phenotype CD8+T cells in the bone marrow

Abstract

CD127 is the IL-7 receptor α-chain and its expression is tightly regulated during T-cell differentiation. We previously showed that the bone marrow (BM) is a key organ for proliferation and maintenance of both antigen-specific and CD44(high) memory CD8(+) T cells. Interestingly, BM memory CD8(+) T cells express lower levels of membrane CD127 than do the corresponding spleen and lymph node cells. We investigated the requirements for CD127 downmodulation by CD44(high) memory-phenotype CD8(+) T cells in the BM of C57BL/6 mice. By comparing genetically modified (i.e. CD127tg, IL-7 KO, IL-15 KO, IL-15Rα KO) with wild-type (WT) mice, we found that the key molecule regulating CD127 downmodulation was IL-15 but not IL-7, and that the intact CD127 gene was required, including the promoter. Indeed, CD127 mRNA transcript levels were lower in CD44(high) CD8(+) T cells from the BM than in those from the spleen of WT mice, indicating organ-specific regulation. Although levels of the CD127 transactivator Foxo1 were low in BM CD44(high) CD8(+) T cells, Foxo1 was not involved in IL-15-induced CD127 downmodulation. Thus, recirculating CD44(high) CD8(+) T cells passing through the BM transiently downregulate CD127 in response to IL-15, with implications for human therapies acting on the IL-7/CD127 axis, for example cytokine treatments in cancer patients.