Mizuko Mamura
,
Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
Jeong-Hwan Yoon
,
Department of Experimental Pathology, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
Susumu Nakae
,
The University of Tokyo, The Institute of Medical Science, Tokyo, Japan
Isao Matsumoto
,
Division of Clinical Immunology, Major of Advanced Biomedical Applications, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
Takayuki Sumida
,
Division of Clinical Immunology, Major of Advanced Biomedical Applications, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
Inkyu Lee
,
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea
Jin Soo Han
,
Institute for the 3Rs, Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, South Korea
Ji Hyeon Ju
,
Department of Internal Medicine, Catholic University of Korea, Seoul, South Korea
Katsuko Sudo
,
Animal Research Center, Tokyo Medical University, Tokyo, Japan
Mitsuyasu Kato
,
Department of Experimental Pathology, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
Masahiko Kuroda
,
Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
Yukari Okubo
,
Department of Dermatology, Tokyo Medical University, Tokyo, Japan
Background: Transforming growth factor-β (TGF-β) plays crucial regulatory roles in T cell-mediated contact hypersensitivity (CHS). Canonical TGF-β signaling pathway is mediated through TGF-β-specific receptor-regulated Smads (R-Smads) and the common Smad, Smad4. However, precise signaling mechanisms whereby TGF-β regulates T cells in CHS are not fully understood.
Objectives: We sought to determine the mechanisms how TGF-β signaling through Smad4 regulates the pathogenic effector T cell subsets in CHS.
Methods: We used Cd4Cre-loxp system to delete Smad4 in T cell-specific manner (Cd4Cre;Smad4fl/fl,+/+). Cd4Cre;Smad4fl/fl,+/+ mice were immunized and sensitized by 1-fluoro-2,4-dinitrobenzene (DNFB).
Results: We found that T cell-specific deletion of Smad4 exacerbated DNFB-induced CHS with significant expansion and infiltration of CD8+ T cells in the draining lymph nodes and the skin lesions. Smad4 deficient CD8+ T cells upregulated Th2 differentiation, regardless of Smad4 genotypes of CD4+ T cells. Smad4 in combination with Smad3 suppressed the expression of a T-box transcription factor, Eomesodermin (Eomes) in CD8+ T cells. Expression of Eomes and the cytotoxic molecules in CD8+ T cells at the early phase of sensitization was significantly upregulated in Cd4Cre;Smad4fl/fl mice compared with control Cd4Cre;Smad4+/+ mice. Cytolytic molecules in CD8+ T cells upregulated by Smad4 deletion induced Th1 cell apoptosis, which resulted in increased Th2.
Conclusions: These data highlight CD8+ T cell-intrinsic Smad4 as the crucial regulator of effector CD4+ T cell subsets in CHS.
