RIKEN IMS AnnualReport 2020
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The vertebrate immune system consists of two components, innate and 31CD1dCD4CD8iNKTpCD8 down‐regulationCD1dCD4CD8iNKTpConstitutive expression of CD8TCR signalsWtCd8‐TgBalanced differentiation of iNKT cell subsetsiNKTiNKT2 skewed differentiationCD8iNKT1↓iNKT2iNKT2↑iNKT17CD8+TCD4iNKTpCD4iNKTpEnhanced TCR signalsDifferentiation of MHC‐I restricted cellsiNKT1iNKT2iNKT17IL‐4 from iNKT2CD8Innate memory‐like CD8+T celladaptive. The adaptive immune system appeared later during evolution, minimally by acquisition of a system for generating pools of lymphocytes with a broad variety of antigen-specificities. Thus, the primary developmental pro-gram of T lymphocytes that occurs in the thymus has been shaped to select useful and non-self-reactive immune soldiers using a sophisticated nuclear program that integrates environmental cues sensed by T cell antigen receptors (TCR). My laboratory has been addressing how TCR signals are sensed and are coupled with cell fate determination programs in the nucleus by using the helper- versus cytotoxic-lineage choice as a model, in which expression of the ThPOK transcription factor serves as a key determinant.CD4 and CD8 glycoproteins serve as co-receptors to assist recognition of peptide antigen presented on class-II and class-I MHC, respectively. While CD8 expression is temporally down-regulated in post-selection thymocyte, CD4 expression is maintained. This difference in the kinetics of expression of the two co-receptors during differentiation of post-selected thymocytes, known as a kinetic signaling model, has been proposed to be a key determinant for the helper- versus cytotoxic-lineage choice. Our current study tested this model by generating a mouse strain in which CD8 is constitutively expressed from a transgene. We found that constitutive CD8 expression drives innate memory-like CD8+ T cell differentiation rather than directing MHC-I restricted cells toward the helper-lineage. This enhanced differentiation of innate memory-like CD8+ T-cells is caused in part by skewed differentiation of the iNKT2 cell subset secreting IL-4. Collectively, our study reveals a novel significance of CD8 down-regulation in fine tuning a balance of iNKT cell subset differentiation to minimize innate memory-like CD8+ T cell differentiation.Figure: Constitutive CD8 expression drives in-nate CD8+ T-cell differentiation via induction of iNKT2 cellsExpression of CD8 is downregulated after receiving TCR mediated positive selection signals. Constitutive CD8 expression from a transgene results in enhanced dif-ferentiation of innate memory-like CD8+ thymocytes in both a cell-intrinsic and -extrinsic manner, the latter being accomplished by an increase in the IL-4 producing iNKT2 subset. These findings shed new light on the rel-evance of CD8 down-regulation in shaping the balance of iNKT cell subsets by modulating TCR signaling.Recent Major PublicationsLiu M, Kuo F, Capistrano KJ, Kang D, Nixon BG, Shi W, Chou C, Do MH, Stamatiades EG, Gao S, Li S, Chen Y, Hsieh JJ, Hakimi AA, Taniuchi I, Chan TA, Li MO. TGF-β suppresses type 2 immunity to cancer. Nature 587, 115-120 (2020)Nomura A, Taniuchi I. The Role of CD8 Downregulation during Thymocyte Differentiation. Trends Immunol 41, 972-981 (2020)Seo W, Shimizu K, Kojo S, Okeke A, Kohwi-Shigematsu T, Fujii SI, Taniuchi I. Runx-mediated regulation of CCL5 via antagonizing two enhancers influences immune cell function and anti-tumor immunity. Nat Commun 11, 1562 (2020)Invited presentationsTaniuchi I. “Pathogenesis of primary immunodeficiency by miss sense mutation in transcription factors” The 48th Annual Meeting of Japanese Society of Clinical Immunology (Tokyo, Japan/Online) October 2020Laboratory for Transcriptional RegulationTeam Leader: Ichiro Taniuchi

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