Aging Impacts Progenitor Cells in the Thymus

The age-related decline of the immune system has several causes, but the involution of the thymus is an important one. The thymus is responsible for the production of mature T cells of the adaptive immune system, but the organ atrophies with age. The supply of new T cells falls off dramatically in later life, and without these reinforcements, the adaptive immune system becomes ever more populated with broken, misconfigured, senescent, exhausted, and outright harmful T cells.

A few research groups and companies are investigating ways to restore the thymus, typically by provoking it to regrow. A number of approaches have been demonstrated to accomplish this goal in mammals, with varying degrees of success and reliability. Only two have been shown to work in humans, the growth hormone approach of Intervene Immune, and sex steroid ablation, as used in prostate cancer and hematopoietic stem cell transplant patients.

Today's open access paper provides confirming evidence for the atrophy of the thymus to be a function of changes in the progenitor cells of the thymic epithelium, responsible for providing daughter somatic cells to populate this tissue. If stem cells and progenitor cells become dysfunctional, a slow atrophy of the surrounding tissues is more or less exactly what one would expect. This is seen in the loss of muscle mass and strength with aging, for example, relating to the declining activity of muscle stem cells. This work is interesting in the context of past demonstrations of cell therapies for thymus regrowth, in which thymic epithelial cells are delivered in animal studies.

Ageing compromises mouse thymus function and remodels epithelial cell differentiation

Ageing of the immune system first manifests as a dramatic involution of the thymus. This is the primary lymphoid organ that generates and selects a stock of immunocompetent T cells. The thymus is composed of two morphological compartments that convey different functions: development of thymocytes and negative selection against self-reactive antigens are both initiated in the cortex before being completed in the medulla. Both compartments are composed of a specialized stromal microenvironment dominated by thymic epithelial cells (TECs).

Thymic size is already compromised in humans by the second year of life, decreases further during puberty, and continuously declines thereafter. With this reduced tissue mass, cell numbers for both lymphoid and epithelial cell compartments decline. This is paralleled by an altered cellular organization of the parenchyma, and the accumulation of fibrotic and fatty changes, culminating in the organ's transformation into adipose tissue. Over ageing, the output of naïve T cells is reduced and the peripheral lymphocyte pool displays progressively worsened T cell populations.

To resolve the progression of thymic structural and functional decline we studied TEC using single-cell transcriptomics across the first year of mouse life. Unexpectedly, we discovered that the loss and quiescence of TEC progenitors are major factors underlying thymus involution. The function of mature thymic epithelial cells is compromised only modestly. Specifically, an early-life precursor cell population, retained in the mouse cortex postnatally, is virtually extinguished at puberty. Concomitantly, a medullary precursor cell quiesces, thereby impairing maintenance of the medullary epithelium. Thus, ageing disrupts thymic progenitor differentiation and impairs the core immunological functions of the thymus.

Comments

A bit off topic, but as a layperson I've always wondered why CD19 targeting CAR T cells wipe out all the CD19 expressing B cells in the blood, but don't attack the cells in the thymus that undergo Promiscuous Gene Expression and express basically every protein for negative selection of maturing T cells?

Posted by: jimofoz at July 1st, 2020 6:47 PM

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