Interleukin-21 Partially Restores T Cell Counts in Aged Mice

In the open access paper I'll point out today, researchers demonstrate a comparatively straightforward way to enhance the diminished functions of the thymus in old mice, and thus partially reverse the dysfunction in immune response that accompanies aging. The thymus might be thought of as an incubator for the varied types of cell belonging to the active immune system that are collectively known as T cells. In childhood the thymus is very active, producing a flood of new cells. Unusually among mammalian organs, however, the thymus atrophies very early in adulthood in a process known as thymic involution, reducing the supply of new T cells to a trickle. This in effect limits the size of the immune system, and that limit becomes an increasing problem as the years pass. Ever more T cells are focused on specific pathogens and ever fewer remain capable of tackling new threats, for example.

Any and all methods that might prove effective in breaking the natural limits on T cells are of interest, given the importance of immune dysfunction in the progression of age-related frailty. The immune system doesn't just fight off invaders: it is also involved in wound healing, destruction of potentially cancerous and senescent cells, and a variety of other necessary tasks. As the effectiveness of the immune system winds down, many contributions to aging and age-related disease accelerate as a result.

How to restore the legions of competent, useful immune cells, however? Destroying the many duplicate cells that are uselessly focused on specific pathogens, and as a consequence take up space to no good end, seems to work based on animal studies carried out to date. That destruction provokes their replacement with competent new cells, albeit at a slow pace, and - fortunately - targeted cell destruction is a going concern these days thanks to the work taking place in the cancer research community. Another possibility is to use the techniques of stem cell medicine to culture large numbers of patient-matched immune cells and infuse them on a regular basis. This is technically well within the grasp of the clinical community, but not yet adopted. Other approaches focus on restoration of the thymus to its childhood state of activity, such as via tissue engineering and transplantation, or reprogramming of thymic cell state with gene therapy.

That brings us to this simpler approach to alter the behavior of the cells making up the thymus, as well as those involved in the many complicated stages that make up the production of T cells. A T cell doesn't just spring into being, but is rather the result of numerous steps of cellular migration and differentiation that starts with thymocytes, a type of progenitor cell in the thymus, before eventually giving rise to forms of T cell. Here, researchers are using a very blunt tool to achieve their results, simply injecting the mice in their study with the cytokine interleukin-21 (IL-21). Eyeing the data, the results look like a temporary doubling or more of relevant counts of cells, but that isn't enough to pull things back to where they were in youth. Still, the outcome is good given that it is such a simple approach:

Interleukin-21 administration to aged mice rejuvenates their peripheral T-cell pool by triggering de novo thymopoiesis

The vaccination efficacy in the elderly is significantly reduced compared to younger populations due to thymic involution and age-related intrinsic changes affecting their naïve T-cell compartment. Interleukin (IL)-21 was recently shown to display thymostimulatory properties. Therefore, we hypothesized that its administration to ageing hosts may improve T-cell output and thus restore a competent peripheral T-cell compartment. We show in this report that administration of recombinant IL-21 (rIL-21) enhances thymopoiesis in aged mice through expansion of both the stromal and responsive thymocytes compartments without the induction of any apparent pathology in peripheral organs.

Enhanced production of naïve T cells improved the T-cell receptor (TCR) repertoire diversity and re-established a pool of naïve CD4+ and CD8+ T cells displaying potent effector functions in response to TCR stimulation. This increase in the availability and potency of naïve T cells augmented the responsiveness of aged mice to vaccination and tumor challenge.

Besides physiological ageing, contraction of the TCR repertoire is commonly observed in patients suffering from infections, cancers, or following bone marrow transplantation. There are currently no effective therapies capable of exerting a positive impact on broadening the spectrum of TCR. Studies involving IL-21R−/− mice clearly showed that IL-21 is dispensable for immune cell development as normal proportions of lymphocytes, monocytes, and granulocytes have been reported. Our data nevertheless suggest that rIL-21 administration to ageing hosts could have potent clinical uses related to its ability to promote the expansion of thymic progenitor cells, which can be further enhanced if combined with other thymostimulatory compounds.

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