title: Smad4 represses the generation of memory-precursor effector T cells but is required for the differentiation of central memory T cells.
abstract: The transcriptional regulation underlying the differentiation of CD8(+) effector and memory T cells remains elusive. Here, we show that 18-month-old mice lacking the transcription factor Smad4 (homolog 4 of mothers against decapentaplegic, Drosophila), a key intracellular signaling effector for the TGF-β superfamily, in T cells exhibited lower percentages of CD44(hi)CD8(+) T cells. To explore the role of Smad4 in the activation/memory of CD8(+) T cells, 6- to 8-week-old mice with or without Smad4 in T cells were challenged with Listeria monocytogenes. Smad4 deficiency did not affect antigen-specific CD8(+) T-cell expansion but led to partially impaired cytotoxic function. Less short-lived effector T cells but more memory-precursor effector T cells were generated in the absence of Smad4. Despite that, Smad4 deficiency led to reduced memory CD8(+) T-cell responses. Further exploration revealed that the generation of central memory T cells was impaired in the absence of Smad4 and the cells showed survival issue. In mechanism, Smad4 deficiency led to aberrant transcriptional programs in antigen-specific CD8(+) T cells. These findings demonstrated an essential role of Smad4 in the control of effector and memory CD8(+) T-cell responses to infection.
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, PR China.
authors.forename: G
authors.initials: G
authors.lastname: Qiu
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, PR China.
authors.forename: C
authors.initials: C
authors.lastname: Hou
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Genetic Laboratory of Development and Diseases, State Key Laboratory of Proteomics, Institute of Biotechnology, 20 Dongdajie, Beijing, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lan
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Han
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Shen
authors.affiliation: Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Science Center, Beijing, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Genetic Laboratory of Development and Diseases, State Key Laboratory of Proteomics, Institute of Biotechnology, 20 Dongdajie, Beijing, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, PR China.
authors.forename: B
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics / Q000276:immunology*
chemical_list: D051901:Smad4 Protein; C490810:Smad4 protein, mouse