Primary development of the immune system at an early life stage requires 29ABCappropriate differentiation and configuration of a variety of immune cells, such as lymphocytes. Decoding of the developmental program of each immune cell from the genome is controlled mainly by the functions of transcription factors. My laboratory has been addressing how transcription factors regulate lymphocyte development and how dysfunction of transcription factors by ge-nome variants causes inborn errors of immunity (IEIs), which are also known as primary immunodeficiencies (PID). We generated several mouse models that harbor mis-sense variants of transcription factors isolated from human IEI patients. In mouse models of missense variants of the Ikaros zinc-finger (IKZF) family proteins, CD62L expression on B lymphocytes was reduced by either the Ikzf1N158S or Ikzf3N159S variants (Figure). Development of hematopoietic stem cells (HSC) was severely impaired by the Ikzf1N158S variant in a cell intrinsic manner.The quality of T lymphocytes in the thymus is censored by processes known as positive and negative selection, in which environmental cues sensed by T cell antigen receptors (TCR) are coupled with a nuclear program by an uncharac-terized mechanism. My laboratory has been attempting to unravel this mecha-nism by using the helper versus cytotoxic lineage choice as a model, in which repression of Zbtb7b and Cd4 genes is a key event. The WRPY peptide motif at the C-terminus of the Runx protein is essential for repression of Zbtb7b and Cd4 genes by recruiting TLE/Groucho corepressor family proteins. Our current study revealed that 1) the terminal tyrosine (Y) in the WRPY motif residue is phosphorylated, 2) this phosphorylation occurs more abundantly in cytotoxic-lineage cells than in helper-lineage cells and is essential for the interaction of Runx proteins with TLE proteins. Thus, we propose a new model that the phos-phorylation status of Runx proteins is a key regulator of T lymphocyte fate deci-sion in the thymus.Figure: Generation and analyses of disease model mice contribute to understanding the pathogenesis of IEIs(A) Loss of CD62L expression on B lymphocytes by Ikzf3N159S and Ikzf1N158S variants. (B) Impaired HSC de-velopment by the heterozygous Ikzf1N158S mutation in young adult mice. (C) Lethality and severe impairment of HSC development in fetal liver of Ikzf1N158S/N158S em-bryos.Recent Major PublicationsChang J, Yamashita M, Padhi AK, Zhang KYJ, Taniuchi I. Impaired tissue homing by the Ikzf3N159S variant is mediated by interfering with Ikaros function. Front Immunol 14, 1239779 (2023)Okuyama K, Nomura A, Nishino K, Tanaka H, Harly C, Chihara R, Harada Y, Muroi S, Kubo M, Kosako H, Taniuchi I. The Majority of the Serine/Threonine Phosphorylation Sites in Bcl11b Protein Are Dispensable for the Differen-tiation of T Cells. J Immunol 210, 1728-1739 (2023)Larange A, Takazawa I, Kakugawa K, Thiault N, Ngoi S, Olive ME, Iwaya H, Seguin L, Vicente-Suarez I, Becart S, Verstichel G, Balancio A, Altman A, Chang JT, Taniuchi I, Lillemeier B, Kronenberg M, Myers SA, Cheroutre H. A regulatory circuit controlled by extranuclear and nuclear retinoic acid receptor α determines T cell activation and function. Immunity 56, 2054-2069 (2023)Invited presentationsTaniuchi I. “Roles of Runx transcription factors during thymocytes cell fate decision” FASEB conference, the Molecular Mechanisms of Immune Cell Development and Function (Sacrament, USA) November 2023Taniuchi I. “Roles of Runx transcription factors during immune system development” IMP research seminar series at MSKCC (New York, USA) October 2023Taniuchi I. “Toward development of improved anti-cancer immunotherapy” 14th annual scientific meeting of SGCC (Singapore, Singapore) July 2023Taniuchi I. “Pathogenesis of immune disorders by dysregulation of the transcription factor function” The 2nd International Symposium of Clinical Immunol-ogy (Kamakura, Japan) May 2023Laboratory for Transcriptional RegulationTeam Leader: Ichiro Taniuchi
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