Journal Article

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

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

2020

Overview

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 (T SCM ) contribute to such attrition is still unclear. Using single cells RNA sequencing and high-dimensional flow cytometry, we demonstrate that T SCM heterogeneity results from differential engagement of Wnt signaling. In humans, aging is associated with the coupled loss of Wnt/β-catenin signature in CD4 T SCM 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 T SCM . Our data thus hint that reversing T SCM 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. Aging is associated with immune attrition that may impact the effectiveness of the immune system to protect the host from pathogens. Here the authors show that immune aging is associated with alterations in the Wnt/β-catenin signaling and reduced stem cell memory T lymphocytes, hinting the Wnt/β-catenin pathway as a potential therapy target.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 13/21 / 13/31 / 38/91 / 631/250/1619/554 / 631/250/2152/1566/1571 / 631/250/516 / 64/60 / Aging / Aging (natural) / Aging - immunology / Animals / Antigens, CD - genetics / Antigens, CD - metabolism / beta Catenin - immunology / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / Flow cytometry / Gene Expression Profiling / Gene sequencing / Heterogeneity / HIV Infections - immunology / Homeostasis / Humanities and Social Sciences / Humans / Immune system / Immunologic Memory / Immunological memory / Immunology / Intercellular Signaling Peptides and Proteins - metabolism / Lymphocytes / Lymphocytes T / Memory cells / Mice / multidisciplinary / Precursor Cells, T-Lymphoid - immunology / Replenishment / Ribonucleic acid / RNA / Science / Science (multidisciplinary) / Signal transduction / Signaling / Stem cells / Thymus / Thymus Gland - immunology / Wnt protein / Wnt Signaling Pathway - genetics / Wnt Signaling Pathway - immunology / β-Catenin