Naturally arising memory-phenotype CD4 <sup>+</sup> T lymphocytes contain an undifferentiated population that can generate T <sub>H</sub> 1, T <sub>H</sub> 17, and T <sub>reg</sub> cells
Memory-phenotype (MP) CD4<sup>+</sup> T lymphocytes develop from naïve cells via self-recognition at homeostasis. While previous studies defined MP cells as a heterogeneous population that comprises T helper 1 (T<sub>H</sub>1)/17-like subsets, functional significance of the T-bet<sup>-</sup> Rorγt<sup>-</sup> subpopulation remains unknown. Here we show that MP lymphocytes as a whole population can differentiate into T<sub>H</sub>1/17/regulatory T (T<sub>reg</sub>) cells to mediate mild and persistent inflammation in lymphopenic environments, whereas naïve cells exhibit strong, T<sub>H</sub>1-dominated responses. Moreover, we demonstrate that MP lymphocytes comprise not only T<sub>H</sub>1/17-differentiated subsets but a polyclonal, transcriptomically immature "undifferentiated" subpopulation at homeostasis. Furthermore, our data argue that while the T-bet<sup>+</sup> Rorγt<sup>-</sup> MP subset is terminally T<sub>H</sub>1-differentiated, its undifferentiated counterpart retains the capacity to rapidly proliferate to differentiate into T<sub>H</sub>1/17/T<sub>reg</sub> cells, with the latter response tonically constrained by preexisting T<sub>reg</sub> cells. Together, our results identify undifferentiated MP CD4<sup>+</sup> T lymphocytes as a unique precursor that has a diverse differentiation potential to generate T<sub>H</sub>1/17/T<sub>reg</sub> cells to contribute to pathogenesis of inflammation.
Authors
- Ziying Yang (ORCID: https://orcid.org/0000-0002-9606-4900)
- Hiroyuki Nagashima (ORCID: https://orcid.org/0000-0001-8405-6746)
- Alan Sher (ORCID: https://orcid.org/0000-0001-7053-2895)
- Shunichi Tayama (ORCID: https://orcid.org/0009-0000-9568-2718)
- Jaeu Yi (ORCID: https://orcid.org/0000-0003-4907-3924)
- Akihisa Kawajiri (ORCID: https://orcid.org/0000-0002-5989-7786)
- Kosuke Sato (ORCID: https://orcid.org/0000-0001-8754-5975)
- Kazuyoshi Ishigaki (ORCID: https://orcid.org/0000-0003-2881-0657)
- Takeshi Kawabe (ORCID: https://orcid.org/0000-0001-7173-4472)
- Yoichiro Iwakura (ORCID: https://orcid.org/0000-0002-9934-5775)
- Naoto Ishii (ORCID: https://orcid.org/0000-0002-0549-8245)
- Hideo Harigae (ORCID: https://orcid.org/0000-0003-4849-7442)
- Jinfang Zhu (ORCID: https://orcid.org/0000-0002-0117-4745)
- Kwang Soon Kim (ORCID: https://orcid.org/0000-0002-6250-1068)
- Jing Li (ORCID: https://orcid.org/0000-0001-8375-7890)
- Keita Koinuma
- Feng Gao (ORCID: https://orcid.org/0009-0008-3280-2434)
- Hye Jin Yoon
- Minami Ishii
Institutions
- Pohang University of Science and Technology (KR)
- National Institutes of Health (US)
- Tokyo University of Science (JP)
- Tohoku University (JP)
- Washington University in St. Louis (US)
- National Institute of Allergy and Infectious Diseases (US)
- RIKEN Center for Integrative Medical Sciences (JP)
- Ajou University (KR)
Publication Details
- Journal
- Science Advances
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1126/sciadv.adq6618
- Citations
- 5
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 1.20
Funders
- Cell Science Research Foundation
- Deutsches Krebsforschungszentrum
- Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- Inamori Foundation
- Astellas Pharma
- Daiichi Sankyo Foundation of Life Science
- Astellas Foundation for Research on Metabolic Disorders
- Japan Allergy Foundation
- National Institutes of Health
- Chugai Pharmaceutical
- Japan Society for the Promotion of Science
- Daiichi Sankyo Europe