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

• Published in: European journal of immunology 2012-05, Vol.42 (5), p.1129-1139
• Main Authors: Quinci, Angela C., Vitale, Sara, Parretta, Elisabetta, Soriani, Alessandra, Iannitto, Maria L., Cippitelli, Marco, Fionda, Cinzia, Bulfone‐Paus, Silvia, Santoni, Angela, Di Rosa, Francesca
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD44; Bone Marrow; Bone Marrow - immunology; CD8-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Down-Regulation; Down-Regulation - immunology; Female; Forkhead Box Protein O1; Forkhead Transcription Factors; Forkhead Transcription Factors - analysis; Hyaluronan Receptors - immunology; Immunologic Memory; Immunology; Interleukin-15; Interleukin-15 - immunology; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Promoter Regions, Genetic; Receptors, Interleukin-7; Receptors, Interleukin-7 - antagonists & inhibitors; Receptors, Interleukin-7 - genetics; Receptors, Interleukin-7 - immunology; Spleen; Spleen - immunology; T‐cell homeostasis; T‐cell memory; T‐cell recirculation; γ‐chain cytokines
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201142019

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 CD44high 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 CD44high 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 CD44high 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 CD44high CD8+ T cells, Foxo1 was not involved in IL‐15‐induced CD127 downmodulation. Thus, recirculating CD44high 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.