TY - JOUR
T1 - Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway
AU - Kared, Hassen
AU - Tan, Shu Wen
AU - Lau, Mai Chan
AU - Chevrier, Marion
AU - Tan, Crystal
AU - How, Wilson
AU - Wong, Glenn
AU - Strickland, Marie
AU - Malleret, Benoit
AU - Amoah, Amanda
AU - Pilipow, Karolina
AU - Zanon, Veronica
AU - Govern, Naomi Mc
AU - Lum, Josephine
AU - Chen, Jin Miao
AU - Lee, Bernett
AU - Florian, Maria Carolina
AU - Geiger, Hartmut
AU - Ginhoux, Florent
AU - Ruiz-Mateos, Ezequiel
AU - Fulop, Tamas
AU - Rajasuriar, Reena
AU - Kamarulzaman, Adeeba
AU - Ng, Tze Pin
AU - Lugli, Enrico
AU - Larbi, Anis
N1 - Funding Information:
We thank Ivy Low (Flow Cytometry Platform), Esther Mok (Multiplex Analysis Platform), Alicia Seok Wei Tay, and Foo Shihui (Genomic Platform) from SIgN Immunomonitoring Platform (BMRC IAF 311006 grant and BMRC transition funds #H16/99/b0/011). We thank BD Biosciences and BioMarketing Services (BMS) for the generous loan of a BD FACS celesta at University of Malaya. We would like to acknowledge Dr. Robert Balderas (BD Biosciences) for his input in antibody panel design and high-dimensional flow cytometry experiments. We thank Dr. Etienne Becht and Dr. Evan W. Newell for the customized t-SNE and UMAP scripts for flow cytometry unbiased analysis. We thank Dr. Petronela Ancuta (University of Montreal) and Dr. Laurent Reina (SIgN) for the critical reading of the paper. The study is supported by a research grant from the Agency for Science, Technology and Research (No. 10-036), by the Singapore Immunology Network and by a Starting Grant from the European Research Council (ERC-StG-2014 PERSYST 640511 to E.L.). A.L. is a scholar of International Society for Advancement of Cytometry (ISAC). R.R. and A.K. are funded by the High Impact Research/Ministry of Higher Education Research Grant, Malaysia (HIR/ MOHE; H-20001-E000001) and the RU grant (UMRG RP029-14HTM). E.R-M was supported by Consejería de Salud y Bienestar Social of Junta de Andalucía through the Nicolás Monardes Program (C-0032/17) and Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Fondos Europeos para el Desarrollo Regional, FEDER, grants PI16/ 00684, PI19/01127, RETICS, Red de Investigación en SIDA (RD16/0025/0020).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/2/10
Y1 - 2020/2/10
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85079242517
U2 - 10.1038/s41467-020-14442-6
DO - 10.1038/s41467-020-14442-6
M3 - Article
C2 - 32041953
AN - SCOPUS:85079242517
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 821
ER -