title: 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.
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur Fondazione Cenci-Bolognetti, University of Rome Sapienza, Rome, Italy.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Quinci
authors.forename: Sara
authors.initials: S
authors.lastname: Vitale
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Parretta
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soriani
authors.forename: Maria L
authors.initials: ML
authors.lastname: Iannitto
authors.forename: Marco
authors.initials: M
authors.lastname: Cippitelli
authors.forename: Cinzia
authors.initials: C
authors.lastname: Fionda
authors.forename: Silvia
authors.initials: S
authors.lastname: Bulfone-Paus
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Rosa
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000032:analysis; D018960:Hyaluronan Receptors / Q000276:immunology; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology
chemical_list: C476399:Cd44 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D018960:Hyaluronan Receptors; D019409:Interleukin-15; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain