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

Nat Commun. 2020 Feb 10;11(1):821. doi: 10.1038/s41467-020-14442-6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / immunology
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • Gene Expression Profiling
  • HIV Infections / immunology
  • Humans
  • Immunologic Memory
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Precursor Cells, T-Lymphoid / immunology*
  • Thymus Gland / immunology
  • Wnt Signaling Pathway / genetics
  • Wnt Signaling Pathway / immunology*
  • beta Catenin / immunology

Substances

  • Antigens, CD
  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • beta Catenin