The Menin-Bach2 axis is critical for regulating CD4 T-cell senescence and cytokine homeostasis.
Although CD4 T-cell senescence plays an important role in immunosenescence, the mechanism behind this process remains unclear. Here we show that T cell-specific Menin deficiency results in the premature senescence of CD4 T cells, which is accompanied by the senescence-associated secretory phenotype after antigenic stimulation and dysregulated cytokine production. Menin is required for the expansion and survival of antigen-stimulated CD4 T cells in vivo and acts by targeting Bach2, which is known to regulate immune homeostasis and cytokine production. Menin binds to the Bach2 locus and controls its expression through maintenance of histone acetylation. Menin binding at the Bach2 locus and the Bach2 expression are decreased in the senescent CD4 T cells. These findings reveal a critical role of the Menin-Bach2 pathway in regulating CD4 T-cell senescence and cytokine homeostasis, thus indicating the involvement of this pathway in the inhibition of immunosenescence.
1] Department of Immunology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan [2] Translational Research Center, Ehime University Hospital, Shitsukawa, Toon, Ehime 791-0295, Japan.
Makoto
M
Kuwahara
Laboratory of Medical Genomics, Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan.
Junpei
J
Suzuki
Laboratory of Medical Genomics, Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan.
Soichi
S
Tofukuji
Department of Infection and Host Defenses, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
Takeshi
T
Yamada
Department of Infection and Host Defenses, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
Makoto
M
Kanoh
Department of Infection and Host Defenses, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
Akira
A
Matsumoto
Department of Immunology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
Saho
S
Maruyama
Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama 230-0045, Japan.
Kohei
K
Kometani
1] Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Tomohiro
T
Kurosaki
Laboratory of Medical Genomics, Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan.
Osamu
O
Ohara
1] Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan [2] CREST, Japan Science and Technology Agency, Chuo-ku, Chiba 260-8670, Japan.
Toshinori
T
Nakayama
1] Department of Immunology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan [2] Translational Research Center, Ehime University Hospital, Shitsukawa, Toon, Ehime 791-0295, Japan [3] Department of Infection and Host Defenses, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan [4] PRESTO, Japan Science and Technology Agency, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
Masakatsu
M
Yamashita
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D016922:Cellular Senescence; D016207:Cytokines / Q000276:immunology*; D005260:Female; D006706:Homeostasis; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D016207:Cytokines; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins