Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway

Hassen Kared, Shu Wen Tan, Mai Chan Lau, Marion Chevrier, Crystal Tan, Wilson How, Glenn Wong, Marie Strickland, Benoit Malleret, Amanda Amoah, Karolina Pilipow, Veronica Zanon, Naomi Mc Govern, Josephine Lum, Jin Miao Chen, Bernett Lee, Maria Carolina Florian, Hartmut Geiger, Florent Ginhoux, Ezequiel Ruiz-MateosTamas Fulop, Reena Rajasuriar, Adeeba Kamarulzaman, Tze Pin Ng, Enrico Lugli, Anis Larbi

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)


The diversity of the naïve T cell repertoire drives the replenishment potential and capacity of memory T cells to respond to immune challenges. Attrition of the immune system is associated with an increased prevalence of pathologies in aged individuals, but whether stem cell memory T lymphocytes (TSCM) contribute to such attrition is still unclear. Using single cells RNA sequencing and high-dimensional flow cytometry, we demonstrate that TSCM heterogeneity results from differential engagement of Wnt signaling. In humans, aging is associated with the coupled loss of Wnt/β-catenin signature in CD4 TSCM and systemic increase in the levels of Dickkopf-related protein 1, a natural inhibitor of the Wnt/β-catenin pathway. Functional assays support recent thymic emigrants as the precursors of CD4 TSCM. Our data thus hint that reversing TSCM defects by metabolic targeting of the Wnt/β-catenin pathway may be a viable approach to restore and preserve immune homeostasis in the context of immunological history.

Original languageEnglish
Article number821
Number of pages17
JournalNature Communications
Issue number1
Publication statusPublished - 10 Feb 2020
Externally publishedYes

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