An Enhancer of the IL-7 Receptor α-Chain Locus Controls IL-7 Receptor Expression and Maintenance of Peripheral T Cells.
The IL-7R plays critical roles in lymphocyte development and homeostasis. Although IL-7R expression is strictly regulated during lymphocyte differentiation and the immune response, little is known regarding its in vivo regulation. To address this issue, we established a mouse line with targeted deletion of the conserved non-coding sequence 1 (CNS1) element found 3.6 kb upstream of the IL-7Rα promoter. We report that IL-7Rα is expressed normally on T and B cells in thymus and bone marrow of CNS1(-/-) mice except for in regulatory T cells. In contrast, these mice show reduced IL-7Rα expression in conventional CD4 and CD8 T cells as well as regulatory T, NKT, and γδ T cells in the periphery. CD4 T cells of CNS1(-/-) mice showed IL-7Rα upregulation in the absence of growth factors and IL-7Rα downregulation by IL-7 or TCR stimulation, although the expression levels were lower than those in control mice. Naive CD4 and CD8 T cells of CNS1(-/-) mice show attenuated survival by culture with IL-7 and reduced homeostatic proliferation after transfer into lymphopenic hosts. CNS1(-/-) mice exhibit impaired maintenance of Ag-stimulated T cells. Furthermore, IL-7Rα upregulation by glucocorticoids and TNF-α was abrogated in CNS1(-/-) mice. This work demonstrates that the CNS1 element controls IL-7Rα expression and maintenance of peripheral T cells, suggesting differential regulation of IL-7Rα expression between central and peripheral lymphoid organs.
Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan;
Akifumi
A
Abe
Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan;
Shizue
S
Tani-ichi
Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan;
Soichiro
S
Shitara
Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
Guangwei
G
Cui
Division of Host Defense, Network Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
Hisataka
H
Yamada
Reproductive Engineering Team, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; and.
Hitoshi
H
Miyachi
Reproductive Engineering Team, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; and.
Satsuki
S
Kitano
Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan;
Takahiro
T
Hara
Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.
Ryo
R
Abe
Division of Host Defense, Network Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
Yasunobu
Y
Yoshikai
Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; ikuta@virus.kyoto-u.ac.jp.
Koichi
K
Ikuta
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D053699:Interleukin-7 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D053699:Interleukin-7 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone