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

Long term immunoprotection or naturally acquired immunity is conferred by memory T cells and is initiated either upon the first exposure to a pathogen or vaccination. The maintenance of this immunological memory for long durations requires the preservation of T cell stemness and the ability of memory T cell compartments to alternate between an active and proliferating state and a quiescent one, depending on whether the individual is re-exposed to the pathogen. The ability of memory T cells to respond to immune challenges is attributed to the diversity of naïve T cell repertoires.  However, aging and the associated prevalence of pathologies lead to the attrition of the immune system and the loss of immunological memory.

Stem cell memory T lymphocytes (Tscm), produced by the generation and programming of naïve T cells, are a discrete but phenotypically detectable population of cells in animals and humans. Tscms possess the ability to differentiate into all subsets of memory and effector T cells. A question of interest is whether CD4 Tscms are affected by aging and exposure to pathogens.

In this publication, Kared, aimed to determine whether aging and/or exposure to infections affected the renewal capability of CD4 Tscm cells. They used high-dimensional flow-cytometry, single-cell RNA sequencing, confocal imaging and functional assays in the study. The authors have established that CD4 Tscm frequencies are reduced due to aging and inflammation, owing to compromised Wnt/β-catenin signatures. They also show that inflammation and aging promote the expression of DKK-1, a natural inhibitor of the Wnt/β-catenin pathway and that CD4 RTE(recent thymic emigrants) are the most likely source of peripheral Tscm. The study concludes that therapeutic targeting of the Wnt/β-catenin pathway is potentially a good approach to rejuvenate CD4 T cell compartments.

Read the article in Nature Communications here.


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